Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1

ABSTRACT

Triazole derivatives of structural formula I are selective inhibitors of the 11β-hydroxysteroid dehydrogenase-1. The compounds are useful for the treatment of diabetes, such as noninsulin-dependent diabetes (NIDDM), hyperglycemia, obesity, insulin resistance, dyslipidemia, hyperlipidemia, hypertension, Metabolic Syndrome, and other symptoms associated with NIDDM.

FIELD OF THE INVENTION

The present invention relates to triazole derivatives as inhibitors ofthe enzyme 11-beta-hydroxysteroid dehydrogenase Type I (11β-HSD-1 orHSD-1) and methods of treatment certain conditions using such compounds.The compounds of the present invention are useful for the treatment ofdiabetes, such as non-insulin dependent Type 2 diabetes mellitus(NIDDM), insulin resistance, obesity, lipid disorders, hypertension, andother diseases and conditions.

BACKGROUND OF THE INVENTION

Diabetes is caused by multiple factors and is most simply characterizedby elevated levels of plasma glucose (hyperglycemia) in the fastingstate. There are two generally recognized forms of diabetes: Type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), in whichpatients produce little or no insulin, the hormone which regulatesglucose utilization, and Type 2 diabetes, or noninsulin-dependentdiabetes mellitus (NIDDM), wherein patients produce insulin and evenexhibit hyperinsulinemia (plasma insulin levels that are the same oreven elevated in comparison with non-diabetic subjects), while at thesame time demonstrating hyperglycemia. Type 1 diabetes is typicallytreated with exogenous insulin administered via injection. However, Type2 diabetics often develop “insulin resistance”, such that the effect ofinsulin in stimulating glucose and lipid metabolism in the maininsulin-sensitive tissues, namely, muscle, liver and adipose tissues, isdiminished. Patients who are insulin resistant but not diabetic haveelevated insulin levels that compensate for their insulin resistance, sothat serum glucose levels are not elevated. In patients with NIDDM, theplasma insulin levels, even when they are elevated, are insufficient toovercome the pronounced insulin resistance, resulting in hyperglycemia.

Insulin resistance is primarily due to a receptor binding defect that isnot yet completely understood. Resistance to insulin results ininsufficient activation of glucose uptake, diminished oxidation ofglucose and storage of glycogen in muscle, inadequate insulin repressionof lipolysis in adipose tissue and inadequate glucose production andsecretion by the liver.

Persistent or uncontrolled hyperglycemia that occurs in diabetics isassociated with increased morbidity and premature mortality. Abnormalglucose homeostasis is also associated both directly and indirectly withobesity, hypertension and alterations in lipid, lipoprotein andapolipoprotein metabolism. Type 2 diabetics are at increased risk ofdeveloping cardiovascular complications, e.g., atherosclerosis, coronaryheart disease, stroke, peripheral vascular disease, hypertension,nephropathy, neuropathy and retinopathy. Therefore, therapeutic controlof glucose homeostasis, lipid metabolism, obesity and hypertension arecritically important in the clinical management and treatment ofdiabetes mellitus.

Many patients who have insulin resistance but have not developed Type 2diabetes are also at a risk of developing symptoms referred to as“Syndrome X” or “Metabolic Syndrome”. Syndrome X or Metabolic Syndromeis characterized by insulin resistance, along with abdominal obesity,hyperinsulinemia, high blood pressure, low HDL and high VLDL. Thesepatients, whether or not they develop overt diabetes mellitus, are atincreased risk of developing the cardiovascular complications listedabove.

Treatment of Type 2 diabetes typically includes physical exercise anddieting. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic β-cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate insulin-resistant tissues. However, dangerously low levels ofplasma glucose can result, and an increased level of insulin resistancecan ultimately occur.

Biguanides increase insulin sensitivity, resulting in some correction ofhyperglycemia. However, many biguanides; e.g., phenformin and metformin,cause lactic acidosis, nausea and diarrhea.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) form a newer classof compounds with the potential for ameliorating hyperglycemia and othersymptoms of Type 2 diabetes. These agents substantially increase insulinsensitivity in muscle, liver and adipose tissue, resulting in partial orcomplete correction of the elevated plasma levels of glucosesubstantially without causing hypoglycemia. The glitazones that arecurrently marketed are agonists of the peroxisome proliferator activatedreceptor (PPAR) gamma subtype. PPAR-gamma agonism is generally believedto be responsible for the improved insulin sensitization that isobserved with the glitazones. Newer PPAR agonists that are beingdeveloped for treatment of Type 2 diabetes and/or dyslipidemia areagonists of one or more of the PPAR alpha, gamma and delta subtypes. Fora review of insulin-sensitizing agents and other mechanisms for thetreatment of Type 2 diabetes, see M. Tadayyon and S. A. Smith, “Insulinsensitisation in the treatment of Type 2 diabetes,” Expert Opin.Investig. Drugs, 12: 307-324 (2003).

There is a continuing need for new methods of treating diabetes andrelated conditions, such as Metabolic Syndrome. The present inventionmeets this and other needs.

SUMMARY OF THE INVENTION

The present invention relates to bicyclo[2.2.2]-oct-1-yl-1,2,4-triazolesof structural formula I

These bicyclo[2.2.2]-octyltriazole derivatives are effective asinhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Theyare therefore useful for the treatment, control or prevention ofdisorders responsive to the inhibition of 11β-HSD1, such as Type 2diabetes, lipid disorders, obesity, atherosclerosis, and MetabolicSyndrome.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also relates to methods for the treatment,control, or prevention of disorders, diseases, or conditions responsiveto inhibition of 11β-HSD1 in a subject in need thereof by administeringthe compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for the treatment orcontrol of Type 2-diabetes, obesity, lipid disorders, atheroselerosis,and Metabolic Syndrome by administering the compounds and pharmaceuticalcompositions of the present invention.

The present invention also relates to methods for treating obesity byadministering the compounds of the present invention in combination witha therapeutically effective amount of another agent known to be usefulto treat the condition.

The present invention also relates to methods for treating Type 2diabetes by administering the compounds of the present invention incombination with a therapeutically effective amount of another agentknown to be useful to treat the condition.

The present invention also relates to methods for treatingatherosclerosis by administering the compounds of the present inventionin combination with a therapeutically effective amount of another agentknown to be useful to treat the condition.

The present invention also relates to methods for treating lipiddisorders by administering the compounds of the present invention incombination with a therapeutically effective amount of another agentknown to be useful to treat the condition.

The present invention also relates to methods for treating MetabolicSyndrome by administering the compounds of the present invention incombination with a therapeutically effective amount of another agentknown to be useful to treat the condition.

The present invention is also concerned with the use of the compounds ofstructural formula I for the treatment hyperglycemia, insulinresistance, Type 2 diabetes, lipid disorders, obesity, atherosclerosis,and Metabolic Syndrome.

The present invention also provides for the use of the compounds ofstructural formula I in the manufacture of a medicament for use in thetreatment of hyperglycemia, insulin resistance, Type 2 diabetes, lipiddisorders, obesity, atherosclerosis, and Metabolic Syndrome.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned withbicyclo[2.2.2]-oct-1-yl-1,2,4-triazole derivatives useful as inhibitorsof 11β-HSD1. Compounds of the present invention are described bystructural formula I:

or a pharmaceutically acceptable salt thereof; wherein

-   each p is independently 0, 1, or 2;-   each n is independently 0, 1, or 2;-   X is selected from the group consisting of a single bond, O,    S(O)_(p), NR⁶,-   R¹ is selected from the group consisting of    -   arylcarbonyl,    -   (CH₂)_(n)-aryl, and    -   (CH₂)_(n)-heteroaryl;        in which aryl and heteroaryl are unsubstituted or substituted        with one to three substituents independently selected from R⁵;-   R² is selected from the group consisting of    -   hydrogen,    -   C₁₋₈ alkyl,    -   C₂₋₆ alkenyl, and    -   (CH₂)_(n)—C₃₋₆ cycloalkyl,        in which alkyl, alkenyl, and cycloalkyl are unsubstituted or        substituted with one to three substituents independently        selected from R⁸ and oxo;-   each R⁴ is independently selected from the group consisting of    -   hydrogen,    -   halogen,    -   hydroxy,    -   oxo,    -   C₁₋₃ alkyl, and    -   C₁₋₃ alkoxy;-   R³ is selected from the group consisting of    -   hydrogen,    -   C₁₋₁₀ alkyl,    -   C₂₋₁₀ alkenyl,    -   (CH₂)_(n)—C₃₋₆ cycloalkyl,    -   (CH₂)_(n)-aryl,    -   (CH₂)_(n)-heteroaryl, and    -   (CH₂)_(n)-heterocyclyl;        in which aryl, heteroaryl, and heterocyclyl are unsubstituted or        substituted with one to three substituents independently        selected from R⁵; and alkyl, alkenyl, and cycloalkyl are        unsubstituted or substituted with one to five groups        independently selected from R⁸ and oxo;-   R⁵ and R⁸ are each independently selected from the group consisting    of    -   hydrogen,    -   formyl,    -   C₁₋₆ alkyl,    -   (CH₂)_(n)-aryl,    -   (CH₂)_(n)-heteroaryl,    -   (CH₂)_(n)-heterocyclyl,    -   (CH₂)_(n)C₃₋₇ cycloalkyl,    -   halogen,    -   OR⁷,    -   (CH₂)_(n)N(R⁷)₂,    -   cyano,    -   (CH₂)_(n)CO₂R⁷,    -   NO₂,    -   (CH₂)_(n)NR⁷SO₂R⁶,    -   (CH₂)_(n)SO₂N(R⁷)₂,    -   (CH₂)_(n)S(O)_(p)R⁶,    -   (CH₂)_(n)SO₂OR⁷,    -   (CH₂)_(n)NR⁷C(O)N(R⁷)₂,    -   (CH₂)_(n)C(O)N(R⁷)₂,    -   (CH₂)_(n)NR⁶C(O)R⁶,    -   (CH₂)_(n)NR⁶CO₂R⁷,    -   O(CH₂)_(n)C(O)N(R⁷)₂,    -   CF₃,    -   CH₂CF₃,    -   OCF₃,    -   OCHCF₂, and    -   OCH₂CF₃;        wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are        unsubstituted or substituted with one to three substituents        independently selected from halogen, hydroxy, C₁₋₄ alkyl,        trifluoromethyl, trifluoromethoxy, and C₁₋₄ alkoxy; and wherein        any methylene (CH₂) carbon atom in R⁵ and R⁸ is unsubstituted or        substituted with one to two groups independently selected from        halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on        the same methylene (CH₂) carbon atom are taken together with the        carbon atom to which they are attached to form a cyclopropyl        group;-   each R⁶ is independently selected from the group consisting of    -   C₁₋₈ alkyl,    -   (CH₂)_(n)-aryl,    -   (CH₂)_(n)-heteroaryl, and    -   (CH₂)_(n)C₃₋₇ cycloalkyl;        wherein alkyl and cycloalkyl are unsubstituted or substituted        with one to five substituents independently selected from        halogen, oxo, C₁₋₄ alkoxy, C₁₋₄ alkylthio, hydroxy, amino; and        aryl and heteroaryl are unsubstituted or substituted with one to        three substituents independently selected from cyano, halogen,        hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C₁₋₄        alkyl, and C₁₋₄ alkoxy;        or two R⁶ groups together with the atom to which they are        attached form a 5- to 8-membered mono- or bicyclic ring system        optionally containing an additional heteroatom selected from O,        S, and NC₁₋₄ alkyl; and-   each R⁷ is hydrogen or R⁶.

In one embodiment of the compounds of the present invention, R² iscyclopropyl, C₁₋₃ alkyl, or C₂₋₃ alkenyl and R¹ is phenyl or naphthyl inwhich phenyl and naphthyl are unsubstituted or substituted with one tothree substituents independently selected from R⁵. In a class of thisembodiment, R⁵ is selected from the group consisting of halogen,hydroxy, trifluoromethyl, trifluoromethoxy, C₁₋₃ alkyl, C₁₋₃ alkoxy,C₁₋₃ alkylthio, and C₁₋₃ alkylsulfonyl. In a subclass of this class, R²is methyl and R⁴ is hydrogen.

In a second embodiment of the compounds of the present invention,

-   X is a single bond;-   R¹ is phenyl or naphthyl in which phenyl and naphthyl are    unsubstituted or substituted with one to three substituents    independently selected from R⁵;-   R² is cyclopropyl, C₁₋₃ alkyl, or C₂₋₃ alkenyl; and-   R³ is C₁₋₆ alkyl unsubstituted or substituted with one to three    substituents independently selected from R⁸ and oxo.

In a class of this second embodiment, R⁵ is selected from the groupconsisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C₁₋₃alkyl, C₁₋₃ alkoxy, C₁₋₃ alkylthio, and C₁₋₃ alkylsulfonyl. In asubclass of this class, R² is methyl and R⁴ is hydrogen. In anotherclass of this embodiment, R⁸ is selected from the group consisting ofhalogen, hydroxy, oxo, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, and phenyl unsubstituted or substituted with one tothree groups independently selected from halogen and trifluoromethyl. Ina subclass of this class, R² is methyl and R⁴ is hydrogen. In a thirdclass of this embodiment, R⁵ is selected from the group consisting ofhalogen, hydroxy, trifluoromethyl, trifluoromethoxy, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ alkylthio, and C₁₋₃ alkylsulfonyl; and R⁸ is selected fromthe group consisting of halogen, hydroxy, oxo, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylsulfonyl, and phenyl unsubstituted or substitutedwith one to three groups independently selected from halogen andtrifluoromethyl. In a subclass of this class, R² is methyl and R⁴ ishydrogen.

In a third embodiment of the compounds of the present invention,

-   X is a single bond;-   R¹ is phenyl or naphthyl in which phenyl and naphthyl are    unsubstituted or substituted with one to three substituents    independently selected from R⁵;-   R² is cyclopropyl, C₁₋₃ alkyl, or C₂₋₃ alkenyl; and-   R³ is phenyl or heteroaryl wherein phenyl and heteroaryl are    unsubstituted or substituted with one with one to three substituents    independently selected from R⁵.

In a class of this embodiment, R² is methyl and R⁴ is hydrogen.

In another class of this embodiment, R³ is phenyl unsubstituted orsubstituted with one with one to three substituents independentlyselected from R⁵. In a subclass of this class, R⁵ is selected from thegroup consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy,C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ alkylthio, and C₁₋₃ alkylsulfonyl. In asubclass of this subclass, R² is methyl and R⁴ is hydrogen.

In a third class of this embodiment, R³ is oxadiazolyl, unsubstituted orsubstituted with one with one to two substituents independently selectedfrom R⁵.

In a subclass of this class, R⁵ is phenyl unsubstituted or substitutedwith one to three substituents independently selected from halogen,hydroxy, C₁₋₄ alkyl, trifluoromethyl, trifluoromethoxy, and C₁₋₄ alkoxy.In a subclass of this subclass, R² is methyl and R⁴ is hydrogen.

Illustrative, but nonlimiting examples, of compounds of the presentinvention that are useful as inhibitors of 11-beta-hydroxysteroiddehydrogenase Type I are the following:

or a pharmaceutically acceptable salt thereof.

As used herein the following definitions are applicable.

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyand alkanoyl, means carbon chains which may be linear or branched, andcombinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike. Where the specified number of carbon atoms permits, e.g., fromC₃₋₁₀, the term alkyl also includes cycloalkyl groups, and combinationsof linear or branched alkyl chains combined with cycloalkyl structures.When no number of carbon atoms is specified, C₁₋₆ is intended.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof, unless the carbon chain is defined otherwise. Examples ofalkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl,1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. Where thespecified number of carbon atoms permits, e.g., from C₅₋₁₀, the termalkenyl also includes cycloalkenyl groups, and combinations of linear,branched and cyclic structures. When no number of carbon atoms isspecified, C₂₋₆ is intended.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl, and the like.

“Cycloalkyl” is a subset of alkyl and means a saturated carbocyclic ringhaving a specified number of carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and the like. A cycloalkyl group generally is monocyclicunless stated otherwise. Cycloalkyl groups are saturated unlessotherwise defined.

The term “alkoxy” refers to straight or branched chain alkoxides of thenumber of carbon atoms specified (e.g., C₁₋₆ alkoxy), or any numberwithin this range [i.e., methoxy (MeO—), ethoxy, isopropoxy, etc.].

The term “alkylthio” refers to straight or branched chain alkylsulfidesof the number of carbon atoms specified (e.g., C₁₋₆ alkylthio), or anynumber within this range [i.e., methylthio (MeS—), ethylthio,isopropylthio, etc.].

The term “alkylamino” refers to straight or branched alkylamines of thenumber of carbon atoms specified (e.g., C₁₋₆ alkylamino), or any numberwithin this range [i.e., methylamino, ethylamino, isopropylamino,t-butylamino, etc.].

The term “alkylsulfonyl” refers to straight or branched chainalkylsulfones of the number of carbon atoms specified (e.g., C₁₋₆alkylsulfonyl), or any number within this range [i.e., methylsulfonyl(MeSO₂—), ethylsulfonyl, isopropylsulfonyl, etc.].

The term “alkylsulfinyl” refers to straight or branched chainalkylsulfoxides of the number of carbon atoms specified (e.g., C₁₋₆alkylsulfinyl), or any number within this range [i.e., methylsulfinyl(MeSO—), ethylsulfinyl, isopropylsulfinyl, etc.].

The term “alkyloxycarbonyl” refers to straight or branched chain estersof a carboxylic acid derivative of the present invention of the numberof carbon atoms specified (e.g., C₁₋₆ alkyloxycarbonyl), or any numberwithin this range [i.e., methyloxycarbonyl (MeOCO—), ethyloxycarbonyl,or butyloxycarbonyl].

“Aryl” means a mono- or polycyclic aromatic ring system containingcarbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.The most preferred aryl is phenyl.

“Heterocycle” and “heterocyclyl” refer to saturated or unsaturatednon-aromatic rings or ring systems containing at least one heteroatomselected from O, S and N, further including the oxidized forms ofsulfur, namely SO and SO₂. Examples of heterocycles includetetrahydrofuran (THE), dihydrofuran, 1,4-dioxane, morpholine,1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine,imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran,oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane,thiomorpholine, and the like.

“Heteroaryl” means an aromatic or partially aromatic heterocycle thatcontains at least one ring heteroatom selected from O, S and N.Heteroaryls thus includes heteroaryls fused to other kinds of rings,such as aryls, cycloalkyls and heterocycles that are not aromatic.Examples of heteroaryl groups include: pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl,pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl,indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl,phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl,quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl,benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl,dibenzofuranyl, and the like. For heterocyclyl and heteroaryl groups,rings and ring systems containing from 3-15 atoms are included, forming1-3 rings.

“Halogen” refers to fluorine, chlorine, bromine and iodine. Chlorine andfluorine are generally preferred. Fluorine is most preferred when thehalogens are substituted on an alkyl or alkoxy group (e.g. CF₃O andCF₃CH₂O).

The term “composition”, as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

The terms “administration of” and “administering a” compound should beunderstood to mean providing a compound of the invention or a prodrug ofa compound of the invention to the individual in need.

Compounds of structural formula I may contain one or more asymmetriccenters and can thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Thepresent invention is meant to comprehend all such isomeric forms of thecompounds of structural formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers such asketo-enol tautomers. The individual tautomers, as well as mixturesthereof, are encompassed within the compounds of structural formula I.

Compounds of structural formula I may be separated into their individualdiastereoisomers by, for example, fractional crystallization from asuitable solvent, for example methanol or ethyl acetate or a mixturethereof, or via chiral chromatography using an optically activestationary phase. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing anasymmetric center of known absolute configuration.

Alternatively, any stereoisomer of a compound of the general structuralformula I may be obtained by stereospecific synthesis using opticallypure starting materials or reagents of known absolute configuration.

In a different aspect of the invention, a pharmaceutical composition isaddressed comprising a compound in accordance with structural formula I,or a pharmaceutically acceptable salt or solvate thereof, in combinationwith a pharmaceutically acceptable carrier. By the term “solvate” ismeant a hydrate, an alcoholate, or other solvate of crystallization.

In another aspect of the invention, a method of treating hyperglycemia,diabetes or insulin resistance in a mammalian patient in need of suchtreatment is addressed, which comprises administering to said patient aneffective amount of a compound in accordance with structural formula Ior a pharmaceutically salt or solvate thereof.

In another aspect of the invention, a method of treating non-insulindependent (Type 2) diabetes mellitus in a mammalian patient in need ofsuch treatment is disclosed comprising administering to the patient ananti-diabetic effective amount of a compound in accordance withstructural formula I.

In another aspect of the invention, a method of treating obesity in amammalian patient in need of such treatment is disclosed comprisingadministering to said patient a compound in accordance with structuralformula I in an amount that is effective to treat obesity.

In another aspect of the invention, a method of treating MetabolicSyndrome in a mammalian patient in need of such treatment is disclosed,comprising administering to said patient a compound in accordance withstructural formula I in an amount that is effective to treat MetabolicSyndrome.

In another aspect of the invention, a method of treating a lipiddisorder selected from the group consisting of dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, andhigh LDL in a mammalian patient in need of such treatment is disclosed,comprising administering to said patient a compound in accordance withstructural formula I in an amount that is effective to treat said lipiddisorder.

In another aspect of the invention, a method of treating atherosclerosisin a mammalian patient in need of such treatment is disclosed,comprising administering to said patient a compound in accordance withstructural formula I in an amount effective to treat atherosclerosis.

In another aspect of the invention, a method of treating a conditionselected from the group consisting of: (1) hyperglycemia, (2) lowglucose tolerance, (3) insulin resistance, (4) obesity, (5) lipiddisorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16)neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19)neuropathy, (20) Metabolic Syndrome, (21) hypertension and otherconditions and disorders where insulin resistance is a component, in amammalian patient in need of such treatment is disclosed, comprisingadministering to the patient a compound in accordance with structuralformula I in an amount that is effective to treat said condition.

In another aspect of the invention, a method of delaying the onset of acondition selected from the group consisting of (1) hyperglycemia, (2)low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipiddisorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16)neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19)neuropathy, (20) Metabolic Syndrome, (21) hypertension and otherconditions and disorders where insulin resistance is a component in amammalian patient in need of such treatment is disclosed, comprisingadministering to the patient a compound in accordance with structuralformula I in an amount that is effective to delay the onset of saidcondition.

In another aspect of the invention, a method of reducing the risk ofdeveloping a condition selected from the group consisting of (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16)neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19)neuropathy, (20) Metabolic Syndrome, (21) hypertension and otherconditions and disorders where insulin resistance is a component in amammalian patient in need of such treatment is disclosed, comprisingadministering to the patient a compound in accordance with structuralformula I in an amount that is effective to reduce the risk ofdeveloping said condition.

In another aspect of the invention, a method of treating a conditionselected from the group consisting of (1) hyperglycemia, (2) low glucosetolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6)dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9)hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12)atherosclerosis and its sequelae, (13) vascular restenosis, (14)pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease,(17) retinopathy, (18) nephropathy, (19) neuropathy, (20) MetabolicSyndrome, (21) hypertension and other conditions and disorders whereinsulin resistance is a component, in a mammalian patient in need ofsuch treatment, comprising administering to the patient an effectiveamount of a compound as defined in structural formula I and a compoundselected from the group consisting of:

-   -   (a) dipeptidyl peptidase-IV (DP-IV) inhibitors;    -   (b) insulin sensitizing agents selected from the group        consisting of (i) PPARγ agonists, (ii) PPARα agonists, (iii)        PPARα/γ dual agonists, and (iv) biguanides;    -   (c) insulin and insulin mimetics;    -   (d) sulfonylureas and other insulin secretagogues;    -   (e) α-glucosidase inhibitors;    -   (f) glucagon receptor antagonists;    -   (g) GLP-1, GLP-1 analogs, and GLP-1 receptor agonists;    -   (h) GIP, GIP mimetics, and GIP receptor agonists;    -   (i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;    -   ( ) cholesterol lowering agents selected from the group        consisting of (i) HMG-CoA reductase inhibitors, (ii)        sequestrants, (iii) nicotinyl alcohol, nicotinic acid and salts        thereof, (iv) inhibitors of cholesterol absorption, (v) acyl        CoA:cholesterol acyltransferase inhibitors, and (vi)        anti-oxidants;    -   (k) PPARδ agonists;    -   (l) antiobesity compounds;    -   (m) ileal bile acid transporter inhibitors;    -   (n) anti-inflammatory agents, excluding glucocorticoids;    -   (o) protein tyrosine phosphatase 1B (PTP-1B) inhibitors; and    -   (p) antihypertensives including those acting on the angiotensin        or renin systems, such as angiotensin converting enzyme        inhibitors, angiotensin II receptor antagonists or renin        inhibitors, such as captopril, cilazapril, enalapril,        fosinopril, lisinopril, quinapril, ramapril, zofenopril,        candesartan, cilexetil, eprosartan, irbesartan, losartan,        tasosartan, telmisartan, and valsartan;        said compounds being administered to the patient in an amount        that is effective to treat said condition.

Dipeptidyl peptidase-WV inhibitors that can be combined with compoundsof structural formula I include those disclosed in WO 03/004498 (16 Jan.2003); WO 03/004496 (16 Jan. 2003); EP 1 258 476 (20 Nov. 2002); WO02/083128 (24 Oct. 2002); WO 02/062764 (15 Aug. 2002); WO 03/000250 (3Jan. 2003); WO 03/002530 (9 Jan. 2003); WO 03/002531 (9 Jan. 2003); WO03/002553 (9 Jan. 2003); WO 03/002593 (9 Jan. 2003); WO 03/000180 (3Jan. 2003); and WO 03/000181 (3 Jan. 2003). Specific DP-IV inhibitorcompounds include isoleucine thiazolidide; NVP-DPP728; P32/98; and LAF237.

Antiobesity compounds that can be combined with compounds of structuralformula I include fenfluramine, dexfenfluramine, phentermine,sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists, cannabinoidCB1 receptor antagonists or inverse agonists, melanocortin receptoragonists, in particular, melanocortin-4 receptor agonists, ghrelinantagonists, and melanin-concentrating hormone (MCH) receptorantagonists. For a review of anti-obesity compounds that can be combinedwith compounds of structural formula I, see S. Chaki et al., “Recentadvances in feeding suppressing agents: potential therapeutic strategyfor the treatment of obesity,” Expert Opin. Ther. Patents, 11: 1677-1692(2001).

Neuropeptide Y5 antagonists that can be combined with compounds ofstructural formula I include those disclosed in U.S. Pat. No. 6,335,345(1 Jan. 2002) and WO 01/14376 (1 Mar. 2001); and specific compoundsidentified as GW 59884A; GW 569180A; LY366377; and CGP-71683A.

Cannabinoid CB1 receptor antagonists that can be combined with compoundsof formula I include those disclosed in PCT Publication WO 03/007887;U.S. Pat. No. 5,624,941, such as rimonabant; PCT Publication WO02/076949, such as SLV-319; U.S. Pat. No. 6,028,084; PCT Publication WO98/41519; PCT Publication WO 00/10968; PCT Publication WO 99/02499; U.S.Pat. No. 5,532,237; and U.S. Pat. No. 5,292,736.

Melanocortin receptor agonists that can be combined with compounds ofstructural formula I include those disclosed in WO 03/009847 (6 Feb.2003); WO 02/068388 (6 Sep. 2002); WO 99/64002 (16 Dec. 1999); WO00/74679 (14 Dec. 2000); WO 01/70708 (27 Sep. 2001); and WO 01/70337 (27Sep. 2001) as well as those disclosed in J. D. Speake et al., “Recentadvances in the development of melanocortin-4 receptor agonists, ExpertOpin. Ther. Patents, 12: 1631-1638 (2002).

In another aspect of the invention, a method of treating a conditionselected from the group consisting of hypercholesterolemia,atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia,hypertriglyceridemia, and dyslipidemia, in a mammalian patient in needof such treatment is disclosed, comprising administering to the patienta therapeutically effective amount of a compound as defined instructural formula I and an HMG-CoA reductase inhibitor.

More particularly, in another aspect of the invention, a method oftreating a condition selected from the group consisting ofhypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalianpatient in need of such treatment is disclosed, wherein the HMG-CoAreductase inhibitor is a statin.

Even more particularly, in another aspect of the invention, a method oftreating a condition selected from the group consisting ofhypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalianpatient in need of such treatment is disclosed, wherein the HMG-CoAreductase inhibitor is a statin selected from the group consisting oflovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin,atorvastatin, itavastatin, and rosuvastatin.

In another aspect of the invention, a method of reducing the risk ofdeveloping a condition selected from the group consisting ofhypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia and dyslipidemia, and the sequelaeof such conditions is disclosed comprising administering to a mammalianpatient in need of such treatment a therapeutically effective amount ofa compound as defined in structural formula I and an HMG-CoA reductaseinhibitor.

In another aspect of the invention, a method for delaying the onset orreducing the risk of developing atherosclerosis in a human patient inneed of such treatment is disclosed comprising administering to saidpatient an effective amount of a compound as defined in structuralformula I and an HMG-CoA reductase inhibitor.

More particularly, a method for delaying the onset or reducing the riskof developing atherosclerosis in a human patient in need of suchtreatment is disclosed, wherein the HMG-CoA reductase inhibitor is astatin.

Even more particularly, a method for delaying the onset or reducing therisk of developing atherosclerosis in a human patient in need of suchtreatment is disclosed, wherein the HMG-Co A reductase inhibitor is astatin selected from the group consisting of: lovastatin, simvastatin,pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, androsuvastatin.

Even more particularly, a method for delaying the onset or reducing therisk of developing atherosclerosis in a human patient in need of suchtreatment is disclosed, wherein the statin is simvastatin.

In another aspect of the invention, a method for delaying the onset orreducing the risk of developing atherosclerosis in a human patient inneed of such treatment is disclosed, wherein the HMG-CoA reductaseinhibitor is a statin and further comprising administering a cholesterolabsorption inhibitor.

More particularly, in another aspect of the invention, a method fordelaying the onset or reducing the risk of developing atherosclerosis ina human patient in need of such treatment is disclosed, wherein theHMG-Co A reductase inhibitor is a statin and the cholesterol absorptioninhibitor is ezetimibe.

In another aspect of the invention, a pharmaceutical composition isdisclosed which comprises

-   (1) a compound according to structural formula I,-   (2) a compound selected from the group consisting of:    -   (a) DP-IV inhibitors;    -   (b) insulin sensitizing agents selected from the group        consisting of (i) PPARγ agonists; (ii) PPARα agonists, (iii)        PPARα/γ dual agonists, and (iv) biguanides;    -   (c) insulin and insulin mimetics;    -   (d) sulfonylureas and other insulin secretagogues;    -   (e) α-glucosidase inhibitors;    -   (f) glucagon receptor antagonists;    -   (g) GLP-1, GLP-1 analogs, and GLP-1 receptor agonists;    -   (h) GIP, GIP mimetics, and GIP receptor agonists;    -   (i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;    -   (j) cholesterol lowering agents selected from the group        consisting of (i) HMG-CoA reductase inhibitors, (ii)        sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt        thereof, (iv) inhibitors of cholesterol absorption, (v) acyl        CoA:cholesterol acyltransferase inhibitors, and (vi)        anti-oxidants;    -   (k) PPARδ agonists;    -   (l) antiobesity compounds;    -   (m) ileal bile acid transporter inhibitors;    -   (n) anti-inflammatory agents other than glucocorticoids;    -   (o) protein tyrosine phosphatase 1B (PTP-1B) inhibitors; and    -   (p) antihypertensives including those acting on the angiotensin        or renin systems, such as angiotensin converting enzyme        inhibitors, angiotensin II receptor antagonists or renin        inhibitors, such as captopril, cilazapril, enalapril,        fosinopril, lisinopril, quinapril, ramapril, zofenopril,        candesartan, cilexetil, eprosartan, irbesartan, losartan,        tasosartan, telmisartan, and valsartan; and-   (3) a pharmaceutically acceptable carrier.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof include, butare not limited to, salts derived from inorganic bases includingaluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.Particularly preferred are the ammonium, calcium, magnesium, potassium,and sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, cyclic amines, and basic ion-exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as acetateor maleate, can be employed. Included are those esters and acyl groupsknown in the art for modifying the solubility or hydrolysischaracteristics for use as sustained-release or prodrug formulations.

It will be understood that, as used herein, references to the compoundsof structural formula I are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

Solvates, and in particular, the hydrates of the compounds of structuralformula I are included in the present invention as well.

The compounds described herein are selective inhibitors of the 11β-HSD1enzyme. Thus, the present invention relates to the use of the 11β-HSD1inhibitors for inhibiting the reductase activity of 11β-hydroxysteroiddehydrogenase, which is responsible for the conversion of cortisone tocortisol. Excess cortisol is associated with numerous disorders,including NIDDM, obesity, dyslipidemia, insulin resistance andhypertension. Administration of the compounds of the present inventiondecreases the level of cortisol and other 11β-hydroxysteroids in targettissues, thereby reducing the effects of excessive amounts of cortisoland other 11β-hydroxysteroids. Inhibition of 11β-HSD1 can be used totreat and control diseases mediated by abnormally high levels ofcortisol and other 11β-hydroxysteroids, such as NIDDM, obesity,hypertension and dyslipidemia. Inhibition of 11β-HSD1 activity in thebrain such as to lower cortisol levels may also be useful to treat orreduce anxiety, depression, and cognitive impairment.

The present invention includes the use of an 11β-HSD1 inhibitor for thetreatment, control, amelioration, prevention, delaying the onset of orreducing the risk of developing the diseases and conditions that aredescribed herein, as mediated by excess or uncontrolled amounts ofcortisol and/or other corticosteroids in a mammalian patient,particularly a human, by the administration of an effective amount of acompound of structural formula I or a pharmaceutically acceptable saltor solvate thereof. Inhibition of the 11β-HSD1 enzyme limits theconversion of cortisone, which is normally inert, to cortisol, which cancause or contribute to the symptoms of these diseases and conditions ifpresent in excessive amounts.

NIDDM and Hypertension:

The compounds of this invention are selective inhibitors of 11β-HSD1over 11β-HSD2. While the inhibition of 11β-HSD1 is useful for reducingcortisol levels and treating conditions related thereto, inhibition of11β-HSD2 is associated with serious side effects, such as hypertension.

Cortisol is an important and well recognized anti-inflammatory hormone,which also acts as an antagonist to the action of insulin in the liver,such that insulin sensitivity is reduced, resulting in increasedgluconeogenesis and elevated levels of glucose in the liver. Patientswho already have impaired glucose tolerance have a greater probabilityof developing Type 2 diabetes in the presence of abnormally high levelsof cortisol.

High levels of cortisol in tissues where the mineralocorticoid receptoris present often lead to hypertension. Inhibition of 11β-HSD1 shifts theratio of cortisol and cortisone in specific tissues in favor ofcortisone.

Administration of a therapeutically effective amount of an 11β-HSD1inhibitor is effective in treating, controlling and ameliorating thesymptoms of NIDDM, and administration of a therapeutically effectiveamount of an 11β-HSD1 inhibitor on a regular basis delays or preventsthe onset of NIDDM, particularly in humans.

Cushing's Syndrome:

The effect of elevated levels of cortisol is also observed in patientswho have Cushing's Syndrome, which is a metabolic disease characterizedby high levels of cortisol in the blood stream. Patients with Cushing'sSyndrome often develop NIDDM.

Obesity, Metabolic Syndrome, Dyslipidemia:

Excessive levels of cortisol have been associated with obesity, perhapsdue to increased hepatic gluconeogenesis. Abdominal obesity is closelyassociated with glucose intolerance, hyperinsulinemia,hypertriglyceridemia, and other factors of Metabolic Syndrome, such ashigh blood pressure, elevated VLDL and reduced HDL. Montague et al.,Diabetes, 2000, 49: 883-888. Thus, the administration of an effectiveamount of an 11β-HSD1 inhibitor is useful in the treatment or control ofobesity. Long-term treatment with an 11β-HSD1 inhibitor is also usefulin delaying or preventing the onset of obesity, especially if thepatient uses an 11β-HSD1 inhibitor in combination with controlled dietand exercise.

By reducing insulin resistance and maintaining serum glucose at normalconcentrations, compounds of the present invention also have utility inthe treatment and prevention of conditions that accompany Type IIdiabetes and insulin resistance, including the Metabolic Syndrome orSyndrome X, obesity, reactive hypoglycemia and diabetic dyslipidemia.

Cognition and Dementia:

Excessive levels of cortisol in the brain may also result in neuronalloss or dysfunction through the potentiation of neurotoxins. Cognitiveimpairment has been associated with aging, and excess levels of cortisolin the brain. See J. R. Seckl and B. R. Walker, Endocrinology, 2001,142: 1371-1376, and references cited therein. Administration of aneffective amount of an 11β-HSD1 inhibitor results in the reduction,amelioration, control or prevention of cognitive impairment associatedwith aging and of neuronal dysfunction. Inhibitors of 11β-HSD1 may alsobe useful to treat anxiety and depression.

Atherosclerosis:

As described above, inhibition of 11β-HSD1 activity and a reduction inthe amount of cortisol are beneficial in treating or controllinghypertension. Since hypertension and dyslipidemia contribute to thedevelopment of atherosclerosis, administration of a therapeuticallyeffective amount of an 11β-HSD1 inhibitor of the present invention maybe especially beneficial in treating, controlling, delaying the onset ofor preventing atherosclerosis.

Effects on Pancreas:

Inhibition of 11β-HSD1 activity in isolated murine pancreatic β-cellsimproves glucose stimulated insulin secretion (B. Davani et al., J.Biol. Chem., 2000, 275: 34841-34844). Glucocorticoids have been shown toreduce insulin secretion in vivo. (B. Billaudel et al., Horm. Metab.Res., 1979, 11: 555-560).

Reduction of Intraocular Pressure:

Recent data suggests a connection between the levels of glucocorticoidtarget receptors and the 11β-HSD enzymes and the susceptibility toglaucoma (J. Stokes et al., Invest. Ophthamol., 2000, 41: 1629-1638).Therefore, inhibition of 11β-HSD1 activity is useful in reducingintraocular pressure in the treatment of glaucoma.

Immunomodulation:

In certain disease states, such as tuberculosis, psoriasis, and evenunder conditions of excessive stress, high glucocorticoid activityshifts the immune response to a humoral response, when in fact a cellbased response may be more beneficial to the patient. Inhibition of11β-HSD1 activity and the attendant reduction in glucocorticoid levelsshifts the immune response toward a cell based response. See D. Mason,Immunology Today, 1991, 12: 57-60, and G. A. W. Rook, Baillièr's Clin.Endocrinol. Metab., 1999, 13: 576-581.

Osteoporosis:

Glucocorticoids can inhibit bone formation, which can result in a netbone loss. 11β-HSD1 has a role in bone resorption. Inhibition of11β-HSD1 is beneficial in preventing bone loss due to osteoporosis. SeeC. H. Kim et al., J. Endocrinol., 1999, 162: 371-379; C. G. Bellows etal., Bone, 1998, 23: 119-125; and M. S. Cooper et al., Bone, 2000, 27:375-381.

Other Utilities:

The following diseases, disorders and conditions can be treated,controlled, prevented or delayed, by treatment with the compounds ofthis invention: (1) hyperglycemia, (2) low glucose tolerance, (3)insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia,(7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia,(10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and itssequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominalobesity, (16) neurodegenerative disease, (17) retinopathy, (18)nephropathy, (19) neuropathy, (20) Metabolic Syndrome, (21) hypertensionand other disorders where insulin resistance is a component.

The above diseases and conditions can be treated using the compounds ofstructural formula I, or the compound can be administered to prevent orreduce the risk of developintg the diseases and conditions describedherein. Since concurrent inhibition of 11β-HSD2 may have deleteriousside effects or may actually increase the amount of cortisol in thetarget tissue where reduction of cortisol is desired, selectiveinhibitors of 11β-HSD1 with little or no inhibition of 11β-HSD2 aredesirable.

The 11β-HSD1 inhibitors of structural formula I generally have aninhibition constant IC₅₀ of less than about 500 nM, and preferably lessthan about 100 nM. Generally, the IC₅₀ ratio for 11β-HSD2 to 11β-HSD1 ofa compound is at least about two or more, and preferably about ten orgreater. Even more preferred are compounds with an IC₅₀ ratio for11β-HSD2 to 11β-HSD1 of about 100 or greater. For example, compounds ofthe present invention ideally demonstrate an inhibition constant IC₅₀against 11β-HSD2 greater than about 1000 nM, and preferably greater than5000 nM.

Compounds of structural formula I may be used in combination with one ormore other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of structuralformula I or the other drugs have utility. Typically the combination ofthe drugs is safer or more effective than either drug alone, or thecombination is safer or more effective than would be expected based onthe additive properties of the individual drugs. Such other drug(s) maybe administered, by a route and in an amount commonly usedcontemporaneously or sequentially with a compound of structural formulaI. When a compound of structural formula I is used contemporaneouslywith one or more other drugs, a combination product containing suchother drug(s) and the compound of structural formula I is preferred.However, combination therapy also includes therapies in which thecompound of structural formula I and one or more other drugs areadministered on different overlapping schedules. It is contemplated thatwhen used in combination with other active ingredients, the compound ofthe present invention or the other active ingredient or both may be usedeffectively in lower doses than when each is used alone. Accordingly,the pharmaceutical compositions of the present invention include thosethat contain one or more other active ingredients, in addition to acompound of structural formula I.

Examples of other active ingredients that may be administered incombination with a compound of structural formula I, and eitheradministered separately or in the same pharmaceutical composition,include, but are not limited to:

-   -   (a) dipeptidyl peptidase IV (DP-IV) inhibitors;    -   (b) insulin sensitizing agents including (i) PPARγ agonists such        as the glitazones (e.g. troglitazone, pioglitazone, englitazone,        MCC-555, rosiglitazone, and the like) and other PPAR ligands,        including PPARα/γ dual agonists, such as KRP-297, and PPARα        agonists such as gemfibrozil, clofibrate, fenofibrate and        bezafibrate, and (ii) biguanides, such as metformin and        phenformin;    -   (c) insulin or insulin mimetics;    -   (d) sulfonylureas and other insulin secretagogues such as        tolbutamide, glipizide, meglitinide and related materials;    -   (e) α-glucosidase inhibitors, such as acarbose;    -   (f) glucagon receptor antagonists such as those disclosed in WO        98/04528, WO 99/01423, WO 00/39088 and WO 00/69810;    -   (g) GLP-1, GLP-1 analogs, and GLP-1 receptor agonists such as        those disclosed in WO00/42026 and WO00/59887;    -   (h) GIP, GIP mimetics such as those disclosed in WO00/58360, and        GIP receptor agonists;    -   (i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists such as        those disclosed in WO 01/23420;    -   (j) cholesterol lowering agents such as (i) HMG-CoA reductase        inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin,        fluvastatin, atorvastatin, itavastatin, rosuvastatin, and other        statins), (ii) bile-acid sequestrants (cholestyramine,        colestipol, and dialkylaminoalkyl derivatives of a cross-linked        dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt        thereof, (iv) inhibitors of cholesterol absorption, such as        ezetimibe and beta-sitosterol, (v) acyl CoA:cholesterol        acyltransferase inhibitors, such as, for example, avasimibe,        and (vi) anti-oxidants, such as probucol;    -   (k) PPARδ agonists, such as those disclosed in WO97/28149;    -   (l) antiobesity compounds such as fenfluramine, dexfenfluramine,        phentermine, sibutramine, orlistat, neuropeptide Y₁ or Y₅        antagonists, CB1 receptor inverse agonists and antagonists, β₃        adrenergic receptor agonists, melanocortin-receptor agonists, in        particular melanocortin-4 receptor agonists, ghrelin        antagonists, and melanin-concentrating hormone (MCH) receptor        antagonists;    -   (m) ileal bile acid transporter inhibitors;    -   (n) agents intended for use in inflammatory conditions other        than glucocorticoids, such as aspirin, non-steroidal        anti-inflammatory drugs, azulfidine, and selective        cyclooxygenase-2 inhibitors;    -   (o) protein tyrosine phosphatase 1B (PTP-1B) inhibitors; and    -   (p) antihypertensives including those acting on the angiotensin        or renin systems, such as angiotensin converting enzyme        inhibitors, angiotensin II receptor antagonists or renin        inhibitors, such as captopril, cilazapril, enalapril,        fosinopril, lisinopril, quinapril, ramapril, zofenopril,        candesartan, cilexetil, eprosartan, irbesartan, losartan,        tasosartan, telmisartan, and valsartan.

The above combinations include a compound of structural formula I, or apharmaceutically acceptable salt or solvate thereof, with one or moreother active compounds. Non-limiting examples include combinations ofcompounds of structural formula I with two or more active compoundsselected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors,PPAR agonists, PTP-1B inhibitors, DP-IV inhibitors, and anti-obesitycompounds.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols and the like. Preferably the compound ofstructural formula I is administered orally.

The effective dosage of the active ingredient varies depending on theparticular compound employed, the mode of administration, the conditionbeing treated and the severity of the condition. Such dosages may beascertained readily by a person skilled in the art.

When treating or preventing the diseases and conditions describedherein, for which compounds of structural formula I are indicated,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about about 0.1 to about 100milligram per kilogram (mpk) of body weight, preferably given as asingle daily dose or in divided doses about two to six times a day. Thetotal daily dosage thus ranges from about 0.1 mg to about 1000 mg,preferably from about 1 mg to about 50 mg. In the case of a typical 70kg adult human, the total daily dose will range from about 7 mg to about350 mg. This dosage may be adjusted to provide the optimal therapeuticresponse.

Another aspect of the present invention relates to a pharmaceuticalcomposition which comprises a compound of structural formula I, or apharmaceutically acceptable salt or solvate thereof, in combination witha pharmaceutically acceptable carrier.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), transdermal, pulmonary (nasal orbuccal inhalation), or nasal administration, although the most suitableroute in any given case will depend on the nature and severity of thecondition being treated and the active ingredient. They may beconveniently presented in unit dosage form and prepared by any of themethods well-known in the art of pharmacy.

The compound of structural formula I can be combined with thepharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. Carriers take a wide variety of forms. Forexample, carriers for oral liquid compositions include, e.g., water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and other components used in the manufacture of oral liquidsuspensions, elixirs and solutions. Carriers such as starches, sugarsand microcrystalline cellulose, diluents, granulating agents,lubricants, binders, disintegrating agents and the like are used toprepare oral solid dosage forms, e.g., powders, hard and soft capsulesand tablets. Solid oral preparations are preferred over oral liquids.

The oral solid dosage forms may also contain a binder such as gumtragacanth, acacia, corn starch or gelatin; excipients such as dicalciumphosphate; a disintegrating agent such as corn starch, potato starch,alginic acid; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, lactose or saccharin. Capsules may also contain aliquid carrier such as a fatty oil.

Various other materials may be present to act as coatings or to modifythe physical form of the dosage unit. For instance, tablets may becoated with shellac, sugar or both.

Tablets may be coated by standard aqueous or nonaqueous techniques. Thetypical percentage of active compound in these compositions may, ofcourse, be varied from about 2 percent to about 60 percent on a w/wbasis. Thus, tablets contain a compound of structural formula I or asalt or hydrate thereof in an amount ranging from as low as about 0.1 mgto as high as about 1.5 g, preferably from as low as about 1.0 mg to ashigh as about 500 mg, and more preferably from as low as about 10 mg toas high as about 100 mg.

Oral liquids such as syrups or elixirs may contain, in addition to theactive ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Parenterals are typically in the form of a solution or suspension,typically prepared with water, and optionally including a surfactantsuch as hydroxypropylcellulose. Dispersions can be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Typicallypreparations that are in diluted form also contain a preservative.

The pharmaceutical injectable dosage forms, including aqueous solutionsand dispersions and powders for the extemporaneous preparation ofinjectable solutions or dispersions, are also sterile and must be fluidto the extent that easy syringability exists; they must be stable underthe conditions of manufacture and storage and are usually preserved. Thecarrier thus includes the solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g. glycerol, propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

Assays: Measurement of Inhibition Constants:

In vitro enzymatic activity was assessed for test compounds via aScintillation Proximity Assay (SPA). In short, tritiated-cortisonesubstrate, NADPH cofactor and titrated compound of structural formula Iwere incubated with 11β-HSD1 enzyme at 37° C. to allow conversion tocortisol to progress. Following this incubation, a preparation ofprotein A coated SPA beads, pre-blended with anti-cortisol monoclonalantibody and a non-specific 11β-HSD inhibitor, such as18β-glycyrrhetinic acid, was added to each well. The mixture was shakenat 15° C. and was then read on a liquid scintillation counter suitablefor 96 well plates. Percent inhibition was calculated relative to anon-inhibited control well and IC₅₀ curves were generated. This assaywas similarly applied to 11β-HSD2, whereby tritiated cortisol and NADwere used as the substrate and cofactor, respectively. To begin theassay, 40 μL of substrate (25 nM ³H-Cortisone+1.25 mM NADPH in 50 mMHEPES Buffer, pH 7.4) was added to designated wells on a 96-well plate.The compound was dissolved in DMSO at 10 mM followed by a subsequent 50fold dilution in DMSO. The diluted material was then titrated 4 fold,seven times. 1 μL of each titrated compound was then added in duplicateto the substrate. To start the reaction, 10 μL of 11β-HSD1 microsomefrom CHO transfectants was added to each well at the appropriateconcentration to yield approximately 10% conversion of the startingmaterial. For ultimate calculation of percent inhibition, a series ofwells were added that represented the assay minimum and maximum: one setthat contained substrate without compound or enzyme (background), andanother set that contained substrate and enzyme without any compound(maximum signal). The plates were spun briefly at a low speed in acentrifuge to pool the reagents, sealed with an adhesive strip, mixedgently, and incubated at 37° C. for 2 h. After incubation, 45 μL of SPAbeads, pre-suspended with anti-cortisol monoclonal antibody and acompound of formula I, were added to each well. The plates were resealedand shaken gently for greater than 1.5 h at 15° C. Data were collectedon a plate based liquid scintillation counter such as a Topcount. Tocontrol for inhibition of anti-cortisol antibody/cortisol binding,substrate spiked with 1.25 nM [3]H cortisol was added to designatedsingle wells. 1 μL of 200 μM compound was added to each of these wells,along with 10 μL of buffer instead of enzyme. Any calculated inhibitonwas due to compound interfering with the cortisol binding to theantibody on the SPA beads.

Assays: Measurement of In Vivo Inhibition:

In general terms, the test compound was dosed orally to a mammal and aprescribed time interval was allowed to elapse, usually between 1 and 24h. Tritiated cortisone was injected intravenously, followed several minlater by blood collection. Steroids were extracted from the separatedserum and analyzed by HPLC. The relative levels of ³H-cortisone and itsreduction product, ³H-cortisol, were determined for the compound andvehicle-dosed control groups. The absolute conversion, as well as thepercentage of inhibition, was calculated from these values.

More specifically, compounds were prepared for oral dosing by dissolvingthem in vehicle (5% hydroxypropyl-beta-cyclodextrin v/v H₂O, orequivalent) at the desired concentration to allow dosing at typically 10mg per kg. Following an overnight fasting, the solutions were dosed toICR mice (obtained from Charles River) by oral gavage, 0.5 mL per doseper animal, with three animals per test group.

After the desired time had passed, routinely either 4 or 16 h, 0.2 mL of3 μM ³H-cortisone in DPBS was injected by tail vein. The animal wascaged for two min followed by euthanasia in a CO₂ chamber. Uponexpiration, the mouse was removed and blood was collected by cardiacpuncture. The blood was set aside in a serum separation tube for no lessthan 30 min at room temperature to allow for adequate coagulation. Afterthe incubation period, blood was separated into serum by centrifugationat 3000×g, 4° C., for 10 min.

To analyze the steroids in the serum, they were first extracted withorganic solvent. A 0.2 mL volume of serum was transferred to a cleanmicrocentrifuge tube. To this a 1.0 mL volume of ethyl acetate wasadded, followed by vigorous vortexing for 1 min. A quick spin on amicrocentrifuge pelleted the aqueous serum proteins and clarified theorganic supernatant. 0.85 mL of the upper organic phase was transferredto a fresh microcentrifuge tube and dried. The dried sample wasresuspended in 0.250 mL of DMSO containing a high concentration ofcortisone and cortisol for analysis by HPLC.

A 0.200 mL sample was injected onto a Metachem Inertsil C-18chromatography column equilibrated in 30% methanol. A slow lineargradient to 50% methanol separated the target steroids; simultaneousmonitoring by UV at 254 nm of the cold standards in the resuspensionsolution acted as an internal standard. The tritium signal was collectedby a radiochromatography detector that uploaded data to software foranalysis. The percent conversion of ³H-cortisone to ³H-cortisol wascalculated as the ratio of AUC for cortisol over the combined AUC forcortisone and cortisol.

Preparation of Compounds of the Invention:

The compounds of structural formula I of the present invention can beprepared according to the procedures of the following Schemes andExamples, using appropriate materials and are further exemplified by thefollowing specific examples. The compounds illustrated in the examplesare not, however, to be construed as forming the only genus that isconsidered as the invention. The Examples further illustrate details forthe preparation of the compounds-of-the present invention. Those skilledin the art will readily understand that known variations of theconditions and processes of the following preparative procedures can beused to prepare these compounds. The instant compounds are generallyisolated in the their neutral form, but the triazole moeity can befurther converted into a pharmaceutically acceptable salt by dissolutionin an organic solvent followed by addition of the appropriate acid andsubsequent evaporation, precipitation, or crystallization. Alltemperatures are degrees Celsius unless otherwise noted. Mass spectra(MS) were measured by electrospray ion-mass spectroscopy (ESMS).

The phrase “standard peptide coupling reaction conditions” meanscoupling a carboxylic acid with an amine using an acid activating agentsuch as EDC, DCC, and BOP in an inert solvent such as dichloromethane inthe presence of a catalyst such as HOBT. The use of protecting groupsfor the amine and carboxylic acid functionalities to facilitate thedesired reaction and minimize undesired reactions is well documented.Conditions required to remove protecting groups are found in standardtextbooks such as Greene, T, and Wuts, P. G. M., Protective Groups inOrganic Synthesis, John Wiley & Sons, Inc., New York, N.Y., 1991. Cbzand BOC are commonly used protecting groups in organic synthesis, andtheir removal conditions are known to those skilled in the art.

Abbreviations Used in the Description of the Preparation of theCompounds of the Present Invention: AIBN 2,2′-azobisisobutyronitrile BOCt-butyloxycarbonyl BBr₃ boron tribromide 9-BBN9-borabicyclo[3.3.1]nonane Bn benzyl nBuLi n-butyl lithium Cbzbenzyloxycarbonyl CDI 1,1′-carbonyldiimidazole MeOTf methyltrifluoromethanesulfonate CH₂Cl₂ dichloromethane CH₂I₂ diiodomethane(COCl)₂ oxalyl chloride Cs₂CO₃ cesium carbonate DAST(diethylamino)sulfur trifluoride DMAP 4-dimethylamino)pyridine DMFN,N-dimethylformamide Et ethyl Et₃N triethylamine EtOAc ethyl acetateEt₂Zn diethylzinc H₂O₂ hydrogen peroxide Me methyl MeCN acetonitrileMeOH methanol mCPBA meta-chloroperbenzoic acid MS mass spectrum NaBH₄sodium borohydride NaHCO₃ sodium hydrogencarbonate NaOAc sodium acetateNBS N-bromosuccinimide Ph phenyl PyBROP bromotripyrrolidinophosphoniumhexafluorophosphate PPh₃ triphenyiphosphine pyr pyridine SOCl₂ thionylchloride TFA trifluoroacetic acid TFFHN,N,N′,N′-tetramethylformamidinium hexafluorophosphate THFtetrahydrofuran TLC thin-layer chromatography TsOH p-toluenesulfonicacid

Reaction Schemes 1-5 illustrate the methods employed in the synthesis ofthe compounds of the present invention of structural formula I. Allsubstituents are as defined above unless indicated otherwise.

Reaction Scheme 1 illustrates a key step in the synthesis of the novelcompounds of structural formula I of the present invention. As shown inreaction Scheme 1, a secondary amide (1-1) (N-Me or N-Et preferred) canbe methylated by heating with neat methyl triflate in order to providean iminoether (1-2). Alternatively other methylating reagents such asmethyl iodide or methyl sulfate may be used neat or in anon-nucleophilic organic solvent. As shown in Scheme 1, abicyclo[2.2.2]octane-1-carboxylic acid (1-3) is converted to an acylhydrazide (1-4) by using the coupling reagent TFFH and hydrazine in thepresence of a tertiary amine base such as triethylamine. Alternatively,other coupling reagents commonly used for preparing amides may be usedfor this tranformation along with hydrazine. Alternatively, abicyclo[2.2.2]octane-1-carboxylic ester can be heated with hydrazine toprepare acyl hydrazides (1-4). The acyl hydrazide (1-4) and iminoether(1-2) thus produced can be heated together in an inert high boilingorganic solvent such as toluene in the presence of a tertiary amine basesuch as triethylamine to provide bicyclo[2.2.2]octyltriazoles (1-5 ofstructural formula I.

Alternatively, the reaction can be conducted in the inverse manner asdescribed by reaction Scheme 2. In this procedure a secondary amide(2-1) is prepared from a bicyclo[2.2.2]octane-1-carboxylic acid using astandard peptide coupling reaction. This compound is methylated to formthe iminoether (2-2) and reacted with an acyl hydrazide as described forreaction Scheme 1 to provide bicyclo[2.2.2]octyltriazoles (2-3) ofstructural formula I.

Reaction Scheme 3 describes an alternate approach to compounds of thepresent invention of structural formula I, in which the key step is thepalladium catalyzed Suzuki coupling reaction between abicyclo[2.2.2]octylbromotriazole (3-1) and an aryl boronic acid toproduce triazoles (3-2) of structural formula I. The preferredconditions use tetrakis(triphenylphosphine)palladium(0) as the catalystin DMF solvent with cesium carbonate, but other catalysts and conditionsmay be employed, as recognized by those skilled in the art.

Reaction Scheme 4 describes yet another synthetic approach to theformation of compounds of structural formula I. Using this procedure,4-(bicyclo[2.2.2]octyl)oxadiazoles (4-1) are dehydratively condensedwith methylamine, either neat in a melt with methylammoniumtrifluoroacetate or in buffered MeOH solution. These reactions are bestperformed at high temperatures in a high pressure reactor to prevent theloss of methylamine.

Reaction Scheme 5 describes yet another synthetic approach to theformation of compounds of structural formula I. Using this procedure,bicyclo[2.2.2]octylcarboxamides (5-1) are converted to iminochlorides(5-2), using a reagent such as oxalyl chloride, thionyl chloride,phosphorus oxychloride or phosphorus pentachloride, optionally in thepresence of DMF. The iminochloride (5-2) is condensed with an aryltetrazole in a high boiling inert organic solvent such as toluene toprovide the triazole (5-3).

Preparation of [2.2.21Bicyclooctyl Intermediates:

The procedures used in the preparation of [2.2.2]bicyclooctylintermediates for use in the preparation of compounds of the presentinvention are provided below.

Intermediate Schemes 1-4 describe the preparation of oxadiazoles, whichare important intermediates for the synthesis of compounds of structuralformula I. They can be converted into compounds of structural formula Iusing, for example, the reactions described in reaction Scheme 4.

Intermediate Scheme 1 shows a preferred method for the preparation ofoxadiazoles via the dehydration of diacyl hydrazides using a dehydratingreagent such as thionyl chloride. Alternatively, other dehydratingreagents such as phosphorus oxychloride, phosphorus pentachloride oroxalyl chloride may be employed. The diacyl hydrazides may be preparedpreferentially from a hydrazide and an activated acid, such as an acidchloride, in the presence of a tertiary amine base. Alternatively,standard peptide coupling reactions may be employed to prepare thediacyl hydrazide from a hydrazide and a carboxylic acid.

Intermediate Scheme 2 shows a useful reagent for the dehydration ofdiacyl hydrazides to oxadiazoles, namely,2-chloro-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium chloride. Thisreagent in a non-polar solvent (methylene chloride is preferred) alongwith a tertiary amine base (triethylamine is preferred) gives thedesired oxadiazole intermediates in an efficient manner.

Intermediate Scheme 3 shows a preferred reagent for the one potformation (from a hydrazide and a carboxylic acid) and dehydration ofdiacyl hydrazides to oxadiazoles:2-chloro-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium chloride. Thisreagent in a non-polar solvent (methylene chloride is preferred) alongwith a tertiary amine base (triethylamine is preferred) gives thedesired oxadiazole intermediates in an efficient manner.

Intermediate Scheme 4 shows an efficient method for the formation ofoxadiazoles from secondary amides and hydrazides. The secondary amide(N-Me or N-Et preferred) can be methylated by heating with neat methyltriflate in order to provide an iminoether. Alternatively othermethylating reagents such as methyl iodide or methyl sulfate may be usedneat or in a non-nucleophilic organic solvent. Heating the iminoetherthus formed in a high boiling inert organic solvent in the presence of ahydrazide affords oxadiazoles as shown in the Scheme.

Intermediate Scheme 5 shows a preferred method for the synthesis ofbicyclo[2.2.2]octane-1-carboxylic acid.

Intermediate Schemes 6 and 7 show preferred methods for the preparationof bicyclo[2.2.2]octane-1-carboxylic acids with a heteroaryl group atthe R³ position as given by structural formula I. Oxadiazoles at the R³position may be prepared by the condensation of abicyclo[2.2.2]octyl-1-carboxylic acid with an amidoxime as shown inIntermediate Scheme 6. A useful reagent for this coupling is CDI.Alternatively, other reagents useful for dehydration or peptide couplingreactions may be employed. Intermediate Scheme 7 illustrates a preferredmethod for the synthesis of an intermediate of compounds of structuralformula I bearing a thiazole group at the R³ position.

Intermediate Schemes 8-14 show preferred methods for the preparation ofbicyclo[2.2.2]octane-1-carboxylic acids intermediates in the synthesisof compounds of structural formula I with various lkyl or alkenyl orsubstituted alkyl groups at the R³ position. A key reaction is theWittig reaction performed on a bicyclo[2.2.2]octane-1-carboxaldehyde, asshown in Intermediate Scheme 8. The double bond in the product of thisreaction may be hydrogenated to generate an alkyl group of varyinglength and character (which will become the R³ substituent in structuralformula I), depending on the Wittig reagent, as shown in IntermediateScheme 9. Alternatively, the double bond can be used to introduce otherfunctionality, such as the hydroxy or fluoro group, as shown inIntermediate Scheme 10. The aldehyde itself may be used to provide thedifluoromethyl group at position R³, as shown in Intermediate Scheme 11.The alkene product of the Wittig reaction can undergo numerous othertransformations, for example, cyclopropanation, as illustrated inIntermediate Scheme 12. Alternatively, the Wittig reagent may contain aremote functional group, for example, a ketal, as illustrated inIntermediate Scheme 13. This functional group may undergo characteristicfunctional group transformations after the Wittig/reduction sequence,for example, the hydrolysis of a ketal to a ketone, as illustrated inIntermediate Scheme 13, or the reduction of a ketal to an alcohol asillustrated in Intermediate Scheme 14. In this manner compounds ofstructural formula I with a variety of different R³ substituents may beobtained. The specific examples given are intended to convey generalprinciples and are not intended to limit the scope of the R³substituents.

General functional group chemical transformations used to preparecompounds of the present invention are illustrated below in thepreparation of specific compounds of the present invention.

These functional group transformations are of a general variety wellunderstood by those skilled in the art.

The following Examples are provided to illustrate the invention and arenot to be construed as limiting the scope of the invention in anymanner.

EXAMPLE 1

3-Methoxy-4-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]phenol(1-F)

Step A:

To a magnetically stirred solution of 4-benzyloxy-2-hydroxybenzonitrile(1-A, WO 00/69841) (7.95 g, 35.3 mmol) and iodomethane (5.43 mL, 87.2mmol) in DMF (90 mL) cooled to −5° was added all at once sodium hydride(60% dispersion, 2.17 g, 54.2 mmol). The mixture was stirred for 30 min,warmed to room temperature and stirred for an additional 2 h. Most ofthe DMF was removed in vacuo, and the residue was partitioned betweenwater and ethyl acetate. The aqueous phase was extracted three timeswith ethyl acetate. The combined organic phases were washed with waterand saturated brine and dried (MgSO₄). The residue after removal of thesolvent in vacuo was triturated with hexane and chromatographed onsilica gel with hexanes —CH₂Cl₂ (2:3) to give4-benzyloxy-2-methoxybenzonitrile (1-B). MS: m/z 240 (M+1); ¹H NMR (500MHz, CDCl₃): δ 7.47 (d, 1H, J=8.4 Hz), 7.36-7.45 (m, 5H), 6.58 (dd, 1H,J=2.3, 8.4 Hz), 6.57 (d, 1H, J=2.3 Hz), 5.10 (s, 2H), 3.88 (s, 3H) ppm.

Step B:

A vigorously stirred suspension of 4-benzyloxy-2-methoxybenzonitrile(1-B) (1.20 g, 5.0 mmol), sodium azide (732 mg, 11.3 mmol), andtriethylamine hydrochloride (1.54 g, 11.3 mmol) in toluene (6 mL) washeated at 1100 for 48 h. The brown suspension was cooled, water (15 mL)was added, and the mixture stirred for 30 min. The organic layer wasseparated and extracted with water (5 mL). The combined aqueous extractswere acidified to about pH 1 with concentrated HCl. The gum thatinitially precipitated solidified upon stirring for 30 min. The solidwas filtered, washed with water, and dried to give5-[4-(benzyloxy)-2-methoxyphenyl]-2H-tetrazole (1-C). ¹H NMR (500 MHz,CDCl₃): δ 12.9 (vbs, 1H), 7.37 (d, 1H, J=8.7 Hz), 7.34-7.48 (m, 5H),6.78 (dd, 1H, J=2.3, 8.7 Hz), 6.70 (d, 1H, J=2.3 Hz), 5.15 (s, 2H), 4.05(s, 3H) ppm.

Step C:

Oxalyl chloride (3.49 ml, 40 mmol) was added dropwise to a solution ofN-methyl-4-pentylbicyclo[2.2.2]octane-1-carboxamide (1-D) (952 mg, 4.0mmol) in dry CH₂Cl₂ at room temperature. After the vigorous gasevolution subsided, the solution was stirred at room temperature for 2h. The CH₂Cl₂ was removed carefully in vacuo at room temperature andthen at 50°. The clear syrupy residue was dissolved in toluene (8 mL)and 5-[4-(benzyloxy)-2-methoxyphenyl]-2H-tetrazole-(1-C) (1.13 g, 4.0mmol) added. The mixture was heated at 120° for 9 h. The mixture wascooled, and the precipitated solid was filtered, washed with toluene anddried to afford the triazole hydrochloride salt. The salt waspartitioned between CH₂Cl₂ and 10% aqueous K₂CO₃. The aqueous phase wasextracted twice with CH₂Cl₂. The combined CH₂Cl₂ extracts were dried(MgSO₄) and evaporated in vacuo. The residue was chromatographed onsilica gel with 5% MeOH/CH₂Cl₂ to give3-[4-(benzyloxy)-2-methoxyphenyl]-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole(1-E). MS: m/z 474 (M+1); ¹H NMR (500 MHz, CDCl₃): δ 7.33-7.47 (m, 6H),6.65 (dd, 1H, J=2.3, 8.5 Hz), 6.60 (d, 1H, J=2.3 Hz), 5.10 (s, 2H), 3.75(s, 3H), 3.48 (s, 3H), 2.08 (m, 6H), 1.51 (m, 6H), 1.00-1.35 (m, 8H),0.89 (t, 3H, J=7.2) ppm.

Step D:

A solution of3-[4-(benzyloxy)-2-methoxyphenyl]-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole(1-E) (272 mg, 0.572 mmol) in MeOH (8 mL) was hydrogenated for 19 h with10% Pd/C catalyst (27 mg) at room temperature and atmospheric pressure.The catalyst was filtered and washed with MeOH. The MeOH was removed invacuo to afford3-methoxy-4-[4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)₄H-1,2,4-triazol-3-yl]phenol(1-F). MS: m/z 384 (M+1); ¹H NMR (500 MHz, DMSO-d₆): δ 9.94 (s 1H), 7.09(d, 1H, J=8.3), 6.53 (d, 1H, J=1.6 Hz), 6.46 (dd, 1H, J=2.2, 8.2 Hz),3.72 (s, 3H), 3.40 (s, 3H), 1.95 (m, 6H), 1.44 (m, 6H), 1.07-1.33 (m,8H), 0.86 (t, 3H, J=7.2).

EXAMPLE 2

3-Methyl-4-[4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]phenol(2-G)

Step A:

(Trimethylsilyl)diazomethane (2M/hexane, 53 mL, 106 mmol) was addedslowly to a solution of 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid(2-A) (20.3 g, 90.6 mmol) in methylene chloride (100 mL) and methanol(40 mL) until the yellow color persisted. After stirring for 10 min atroom temperature, the solution was concentrated in vacuo to give methyl4-pentylbicyclo[2.2.2]octane-1-carboxylate (2-B). ¹H NMR (500 MHz,CDCl₃): δ 0.89 (t, 3H); 1.20 (m, 8H); 1.39 (m, 6H); 1.77 (m, 6H); 3.65(s, 3H) ppm.

Step B:

Hydrazine (anhydrous, 103 mL, 88.7 mmol) was added to a solution ofmethyl 4-pentylbicyclo[2.2.2]octane-1-carboxylate (2-B) in ethyleneglycol (180 mL) and the mixture was stirred under reflux for 17 h. Aftercooling to room temperature, the mixture was poured into water (1500 mL)and extracted with methylene chloride (3×600 mL). The combined extractswere washed twice with water, brine, dried (MgSO₄) and concentrated invacuo to provide 4-pentylbicyclo[2.2.2]octane-1-carbohydrazide (2-C). ¹HN (500 MHz, CDCl₃): δ 0.90 (t, 3H); 1.21 (m, 8H); 1.43 (m, 6H); 1.74 (m,6H); 3.85 (broad s, 2H); 6.81 (broad s, 1H) ppm.

Step C:

2-Chloro-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium chloride (5.07 g,30.0 mmol) was added to a solution of 2-methyl-4-methoxybenzoic acid(2-D) (856 mg, 5.0 mmol) and4-pentylbicyclo[2.2.2]octane-1-carbohydrazide (2-C) (1.25 g, 5.25 mmol)in methylene chloride (60 mL) followed by triethylamine (8.36 mL, 60mmol) and the mixture stirred at room temperature for 48 h. The mixturewas diluted with methylene chloride and washed with water, 1N HCl, 10%NaHCO₃, brine, dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, hexane:ethyl acetate,9: 1) to give2-(4-methoxy-2-methylphenyl)-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole(2-E) Mass spectrum: 369 (M+1); ¹H NMR (500 MHz, CDCl₃): δ 0.93 (t, 3H);1.27 (m, 8H); 1.56 (m, 6H); 2.03 (m, 6H); 2.70 (s, 3H); 3.89 (s, 3H);6.86 (m, 2H); 7.89 (d, 1H) ppm.

Step D:

2-(4-Methoxy-2-methylphenyl)-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole(2-E) (988 mg, 2.68 mmol), methylammonium trifluoroacetate (9.72 g, 67mmol, prepared by combining equimolar amounts of methylamine andtrifluoroacetic acid in ether followed by concentration in vacuo), andmethylamine (2M/MeOH, 33 mL, 67 mmol) were stirred together in a glassbomb at 150° C. for 114 h. The mixture was concentrated in vacuo and theresidue partitioned with methylene chloride and water. The aqueous phasewas extracted with methylene chloride and the combined extracts washedwith brine, dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, ethyl acetate:hexane,7:3, then 9:1) to give3-(4-methoxy-2-methylphenyl)₄-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)₄H-1,2,4-triazole(2-F). Mass spectrum: 382 (M+1); ¹H NMR (500 MHz, CDCl₃): δ 0.93 (t,3H); 1.27 (m, 8H); 1.56 (m, 6H); 2.12 (m, 6H); 2.18 (s, 3H); 3.49 (s,31); 3.87 (s, 3H); 6.85 (m, 2H); 7.24 (d, 1H) ppm.

Step E:

Boron tribromide (1M/CH₂Cl₂, 3.21 mL, 3.21 mmol) was added to a solutionof3-(4-methoxy-2-methylphenyl)₄-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole(2-F) (410 mg, 1.07 mmol) in methylene chloride (6 mL) at 0° C. Themixture was stirred at room temperature for 2 h. The solution was washedwith water, 10% NaHCO₃, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by preparative TLC (silica gel, MeOH:methylenechloride, 5:95) to provide3-methyl-4-[4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)₄H-1,2,4-triazol-3-yl]phenol(2-G). Mass spectrum: 393 (M+1); ¹H NMR (500 MHz, CDCl₃): δ 0.93 (t,3H); 1.27 (m, 8H); 1.56 (m, 6H); 1.97 (s 3H); 2.12 (m, 6H); 3.50 (s,3H); 6.65 (m, 2H); 6.98 (d, 1H) ppm.

EXAMPLE 3

3-Chloro-4-[4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]phenol(3-G)

Step A:

Oxalyl chloride (505 μL, 5.79 mmol) was added dropwise to a mixture of4-pentylbicyclo[2.2.2]octane-1-carboxylic acid (3-A) in methylenechloride (10 mL). The solution was stirred at room temperature for 3 hand then concentrated in vacuo to give4-pentylbicyclo[2.2.2]octane-1-carbonyl chloride (3-B). ¹H NMR (500 MHz,CDCl₃): δ 0.90 (t, 3H); 1.21 (m, 8H); 1.45 (m, 6H); 1.88 (m, 6H) ppm.

Step B:

N,N-Diisopropylethylamine (1.44 mL, 11.1 mmol) was added to a mixture of4-pentylbicyclo[2.2.2]octane-1-carboxylic acid (3-A) (1.09 g, 4.45 mmol)and methylamine hydrochloride (1.5 g, 22.3 mmol) in methylene chloride(10 mL) was added and the mixture stirred at room temperature for 18 h.After diluting with methylene chloride, the mixture was washed withwater, brine, dried (MgSO₄) and concentrated in vacuo to giveN-methyl-4-pentylbicyclo[2.2.2]octane-1-carboxamide (3-C). ¹H NMR (500MHz, CDCl₃): δ 0.91 (t, 3H); 1.22 (m, 8H); 1.43 (m, 6H); 1.77 (m, 6H);2.82 (d, 3H) ppm.

Step C:

Oxalyl chloride (846 μL, 9.7 mmol) was added dropwise to a solution ofN-methyl-4-pentylbicyclo[2.2.2]octane-1-carboxamide (3-C) (230 mg, 0.97mmol) in methylene chloride (2.0 mL) and the mixture stirred at roomtemperature for 4 h. The solvent and excess reagent were removed invacuo to provide N-methyl-4-pentylbicyclo[2.2.2]octane-1-carboximidoylchloride (3-D). Toluene (1.5 mL) was added followed by5-(2-chloro-4-methoxyphenyl)-1H-tetrazole (3-E) (204 mg, 0.97 mmol) andthe mixture refluxed for 18 h. The reaction was cooled to roomtemperature and the precipitate was filtered, washed with cold toluene,hexane, dissolved in methylene chloride, dried (MgSO₄) and concentratedin vacuo to provide3-(2-chloro-4-methoxyphenyl)-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole(3-F). Mass spectrum: 402 (M+1); ¹H NMR (500 MHz, CDCl₃): δ 0.94 (t,3H); 1.27 (m, 8H); 1.56 (m, 6H); 2.13 (m, 6H); 3.56 (s, 3H); 3.89 (s,3H); 6.95 (dd, 1H); 7.07 (d, 1H); 7.43 (d, 1H).

Step D:

Boron tribromide (135 μL, 1.43 mmol) was added dropwise to a solution of3-(2-chloro-4-methoxyphenyl)-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)₄H-1,2,4-triazole(3-F) (287 mg, 0.714 mmol) in methylene chloride (5 mL) at 0° C. Themixture was stirred at room temperature for 2.5 h. The solution waswashed with water, 10% NaHCO₃, dried (MgSO₄) and concentrated in vacuoand the residue purified by column chromatography (silica gel, 5%MeOH/methylene chloride) to provide3-chloro-4-[4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]phenol(3-G). Mass spectrum: 388 (M+1); ¹H NMR (500 MHz, CDCl₃): δ 0.93 (t,3H); 1.26 (m, 8H); 1.56 (m, 6H); 2.13 (m, 6H); 3.58 (s, 3H); 6.69 (dd,1H); 6.92 (d, 1H); 7.09 (d 1H) ppm.

EXAMPLE 4

5-(4-{1-Methyl-5-[2-(trifluoromethyl)phenyl]-1-H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)pentan-2-ol(4-J)

Step A:

[2-(2-Methyl-1,3-dioxolan-2-yl)ethyl](triphenyl)phosphonium bromide(4-A, Synthesis: 532 (1986)) (5.99 g, 12.7 mmol) was stirred in dry THF(200 mL). Potassium bis(trimethylsilyl)amide (20.4 mL, 2M soln intoluene, 10.2 mmol) was added. The reaction was allowed to stir for 30min. The reaction mixture was then cooled to −78° C. Methyl4-formylbicyclo[2.2.2]octane-1-carboxylate was added at −78° C. bycannula. The reaction was allowed to warm to room temperature overnight.The volume was reduced by evaporation of THF in vacuo. 100 mL of waterwas added. The mixture was then layered with 100 mL of diethyl ether.The ether was extracted and dried (MgSO₄). The product (methyl4-[(1E)-3-(2-methyl-1,3-dioxolan-2-yl)prop-1-enyl]bicyclo[2.2.2]octane-1-carboxylate(4-B)) was purified by flash chromatography on silica gel with 10/90ethyl acetate-hexane mixture.

Step B:

Methyl4-[(1E)-3-(2-methyl-1,3-dioxolan-2-yl)prop-1-enyl]bicyclo[2.2.2]octane-1-carboxylate(4-B) (1.1 g) was stirred in ethanol (75 mL). A spatula tip scoop of 10%Pd on carbon (150 mg) was added. A hydrogen balloon was added and themixture was stirred under hydrogen atmosphere for 3 h. Thepalladium-on-carbon was filtered and the ethanol was removed in vacuo toyield methyl4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]octane-1-carboxylate(4-C).

Step C:

Methyl4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]octane-1-carboxylate(4-C) (1.0 g, 3.38 mmol) was stirred in a solution of 90% methanol and10% water (50 mL). Excess potassium hydroxide (2.0 g) was added. Themixture was refluxed overnight. The cooled mixture was acidified with 1Nhydrochloric acid (100 mL) and then washed twice with ethyl acetate (100mL). The combined organic layers were dried (MgSO₄). Ethyl acetate wasremoved in vacuo yielding pure4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]octane-1-carboxylicacid (4-D).

Step D:

4-[3-(2-Methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]octane-1-carboxylicacid (4-D) (0.200 g, 0.708 mmol) was combined with2-(trifluoromethyl)benzoic hydrazide (4-E) (0.173 g, 0.847 mmol) andazeotroped twice from toluene. The mixture was then stirred in drymethylene chloride (10 mL). 2-Chloro-1,3-dimethylimidazolinium chloride(4-F) (0.718 g, 4.25 mmol) was added followed by 1.184 mL oftriethylamine. The reaction was allowed to stir for 2 h. The reactionwas diluted with methylene chloride and was washed with water. Theresulting oxadiazole,2-{4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]oct-1-yl}-5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazole(4-G) was purified by flash chromatography on silica gel with 50/50ethyl acetate-hexane mixture.

Step E:

2-{4-[3-(2-Methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]oct-1-yl}-5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazole(4-G) (0.158 g) was stirred in a mixure of 90% acetone/10% water (20mL). p-Toluenesulfonic acid (10 mg) was added to the solution. Thereaction was heated to reflux for 1 h. The volume was reduced byevaporation of acetone in vacuo. The mixture was then layered with ethylacetate (25 mL) and saturated sodium bicarbonate solution (25 mL). Theethyl acetate layer was extracted and dried (MgSO₄). Solvent was removedin vacuo to afford pure5-(4-{5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]oct-1-yl)pentan-2-one(4-H).

Step F:

5-(4-{5-[2-(Trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]oct-1-yl)pentan-2-one(4-H) (0.072 g) was stirred in methanol (2 mL) at 0° C. Sodiumborohydride (−20 mg) was added. The reaction was allowed to stir to roomtemperature. The mixture was then layered with ethyl acetate (15 mL) andwater (15 mL). The ethyl acetate layer was extracted and dried (MgSO₄).Solvent was removed in vacuo to afford pure5-(4-{5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]oct-1-yl)pentan-2-ol(4-I).

Step G:

5-(4-{5-[2-(Trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]oct-1-yl)pentan-2-ol(4-D) (50 mg) was placed in a sealed vial in a solution of 2Mmethylamine in methanol (2.5 mL). A small spatula scoop of methylamineTFA salt was added and the vial was sealed. The sealed vial was heatedto 150° C. for 3 d. The reaction was diluted with ethyl acetate (15 mL),washed with water (15 mL), and dried (MgSO₄). Ethyl acetate was removedin vacuo. The product,5-(4-{1-methyl-5-[2-(trifluoromethyl)phenyl]-1-H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)pentan-2-ol(4-J), was purified by preparative reverse phase HPLC on a C-18 silicagel column using a gradient of acetonitrile-water buffered with 0.1%trifluoroacetic acid. The effluent containing the pure triazole was madebasic with 10% NaHCO₃, evaporated in vacuo to remove most of theacetonitrile, and extracted with methylene chloride. The organic extractwas dried (MgSO₄) and evaporated, and the residue dried under vacuum toprovide the desired compound. MS (ESI+)=422.5 (M+1); ¹H NMR (500 MHz,CDCl₃): δ 1.21 (2H, m), 1.23 (3H, d, J=6.5 Hz), 1.29 (2H, m), 1.57 (6H,m), 2.13 (6H, m), 3.47 (3H, s), 3.85 (1H, m), 7.51 (1H, m), 7.70 (2H,m), 7.85 (1H, m) ppm.

EXAMPLE 5

3-Chloro-4-{5-[4-(4-hydroxypentyl)bicyclo[2.2.2]oct-1-yl]-1-methyl-1-H-1,2,4-triazol-3-yl}phenol(5-K)

Step A:

4-[3-(2-Methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]octane-1-carboxylicacid (4-D) (0.300 g, 1.06 mmol) was combined with2-chloro-4-methoxybenzohydrazide (5-E) (0.255 g, 1.275 mmol) andazeotroped twice from toluene. The mixture was then stirred in drymethylene chloride (15 mL). 2-Chloro-1,3-dimethylimidazolinium chloride(5-F) (1.075 g, 6.36 mmol) was added followed by 1.77 mL oftriethylamine. The reaction was allowed to stir for 2 h. The reactionwas diluted with methylene chloride and was washed with water. Theresulting oxadiazole,2-(2-chloro-4-methoxyphenyl)-5-{4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]oct-1-yl}-1,3,4-oxadiazole(5-G) was purified by flash chromatography on silica gel with 50/50ethyl acetate-hexane mixture.

Step B:

2-(2-Chloro-4-methoxyphenyl)-5-{4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]oct-1-yl}-1,3,4-oxadiazole(5-G) (0.200 g) was stirred in a mixure of 90% acetone/10% water (20mL). p-Toluenesulfonic acid (15 mg) was added to the solution. Thereaction was heated to reflux for 1 h. The volume was reduced byevaporation of acetone in vacuo. The mixture was then layered with ethylacetate (25 mL) and saturated sodium bicarbonate solution (25 mL). Theethyl acetate layer was extracted and dried (MgSO₄). Solvent was removedin vacuo to afford pure5-{4-[5-(2-chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-one(5-H).

Step C:

5-{4-[5-(2-Chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-one(5-H) (0.150 g, 0.373 mmol) was stirred in methanol (5 mL) at 0° C.Sodium borohydride (0.0169 g, 0.448 mmol) was added. The reaction wasallowed to stir to room temperature. The mixture was then layered withethyl acetate (20 mL) and water (20 mL). The ethyl acetate layer wasextracted and dried (MgSO₄). Solvent was removed in vacuo to afford5-{4-[5-(2-chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-ol(5-I).

Step D:

5-{4-[5-(2-Chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-ol(5-1) (50 mg) was placed in a sealed vial in a solution of 2Mmethylamine in methanol (2.5 mL). A small spatula scoop of methylamineTFA salt was added and the vial was sealed. The sealed vial was heatedto 150° C. for 24 h. The reaction was diluted with ethyl acetate (15mL), washed with water (15 mL), and dried (MgSO₄). Ethyl acetate wasremoved in vacuo. The product,5-{4-[5-(2-chloro-4-methoxyphenyl)-1-methyl-1-H-1,2,4-triazol-3-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-ol(5-J), was purified by preparative TLC with 5% methanol/95% ethylacetate.

Step E:

5-{4-[5-(2-Chloro-4-methoxyphenyl)-1-methyl-1-H-1,2,4-triazol-3-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-ol(5-J) (0.036 g, 0.086 mmol) was placed in a small vial with 0.5 mL ofDMF. Sodium ethanethiolate (0.0218 g, 0.260 mmol) was added to thesolution. The vial was sealed and heated to 1000 C for 1.5 h. Theincomplete reaction required another 1.5 equivalents of sodiumethanethiolate (0.011 g). The vial was resealed and heated at 1000 C for1 h. The product,3-chloro-4-{5-[4-(4-hydroxypentyl)bicyclo[2.2.2]oct-1-yl]-1-methyl-1-H-1,2,4-triazol-3-yl}phenol(5-K) was purified by preparative reverse phase HPLC on a C-18 silicagel column using a gradient of acetonitrile-water buffered with 0.1%trifluoroacetic acid. The effluent containing the pure triazole was madebasic with 10% NaHCO₃, evaporated in vacuo to remove most of theacetonitrile, and extracted with methylene chloride. The organic extractwas dried (MgSO₄) and evaporated, and the residue dried under vacuum toprovide the desired compound. MS (ESI⁺)=404.4 (M+1).

EXAMPLE 6

5-{4-[5-(2-chloro-4-hydroxyphenyl)-4-methyl-4H-1,2,4-triazol-3-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-one(6-L)

3-Chloro-4-{5-[4-(4-hydroxypentyl)bicyclo[2.2.2]oct-1-yl]4-methyl-4H-1,2,4-triazol-3-yl}phenol(5-K) (0.0035 g, 0.00869 mmol) was stirred in 0.5 mL of dry methylenechloride over activated 4 A sieves. N-methylmorpholine N-oxide (0.0015g, 0.013 mmol) was added. The mixture was allowed to stir under N₂ for15 min. Tetrapropylammonium perruthenate (0.00112 g, 0.00956 mmol) wasadded and the reaction was allowed to stir for 2 h. The mixture wasfiltered through celite filtering agent. The product,5-{4-[5-(2-chloro-4-hydroxyphenyl)-4-methyl-4H-1,2,4-triazol-3-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-one(6-L), was purified by preparative reverse phase HPLC on a C-18 silicagel column using a gradient of acetonitrile-water buffered with 0.1%trifluoroacetic acid. The effluent containing the pure triazole wasbasified with 10% NaHCO₃, evaporated in vacuo to remove most of theacetonitrile, and extracted with methylene chloride. The organic extractwas dried (MgSO₄) and evaporated, and the residue dried under vacuum toprovide the desired compound. MS (ESI⁺)=402.3 (M+1).

EXAMPLE 7

3-(4-Fluorophenyl)-5-[4-[4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl]bicyclo[2.2.2]oct-1-yl]-1,2,4-oxadiazole(7-F)q2

Step A:

To a suspension of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylicacid (7-A) (0.906 g, 4.27 mmol) in dichloromethane (20 mL) was added1,1′-carbonyldiimidazole (1.04 g, 6.41 mmol). The reaction turned into aclear solution instantly with evolving of gas. After the mixture wasstirred at room temperature for 1 h, 4-fluorobenzamidoxime was added(1.98 g, 12.8 mmol). Stirring was continued overnight. The mixture wasthen concentrated and the residue was refluxed in toluene for 16 h. Themixture was concentrated and the residue was purified by columnchromatography using hexane/ethyl acetate as eluent (7/1) to give methyl4-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octane-1-carboxylateacid (7-B) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 1.96-1.99 (m,6H), 2.08-2.14 (m, 6H), 3.71 (s, 3H), 7.16-7.20 (m, 2H), 8.08-8.10 (m,2H) ppm. ESI-MS m/z (M+H) 349.2.

Step B:

The ester (7-B) (1.01 g, 3.06 mmol) was treated with KOH (0.52 g, 9.18mmol) in methanol/water (95/5, 20 mL). After it was heated at 60° C. for12 h, the reaction mixture was concentrated, diluted with water,extracted twice with ethyl acetate. The aqueous layer was acidified with1N HCl aqueous solution and a white solid precipitated out. The solid4-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octane-1-carboxylicacid (7-C) was collected and further dried by co-evaporating withtoluene. ESI-MS nt/z (M+H) 317.2.

Step C:

A mixture of the acid (7-C) (138.9 mg, 0.439 mmol) and2-(trifluoromethyl)benzoic hydrazide (7-D) (89.7 mg, 0.439 mmol) wasfirst co-evaporated with toluene three times. Dichloromethane (7 mL) wasadded to the mixture as solvent. To the resulting suspension was added2-chloro-1,3-dimethylimidazolinium chloride (743 mg, 4.39 mmol) followedby triethylamine (1.2 mL, 8.78 mmol). The mixture was allowed to stir atroom temperature under nitrogen for 48 h to ensure the completion of thereaction. The reaction mixture was then diluted with dichloromethane,washed with water, 1N HCl, saturated sodium bicarbonate aqueoussolution, and lastly brine. The organics were dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified bycolumn chromatography using hexane/ethyl acetate (3/1) as eluent to give3-(4-fluorophenyl)-5-(4-{5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole(7-E) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 2.25 (s, 12H), 7.21(t, J=8.7 Hz, 2H), 7.74-7.76 (m, 2H), 7.91 (m, 1H), 8.11-8.15 (m, 3H)ppm. ESI-MS m/z (M+H) 485.2.

Step D:

A mixture of above 1,2,4-oxadiazole (7-E) (115.2 mg, 0.238 mmol) and thetrifluoroacetic acid salt of methylamine (1.73 g, 11.9 mmol) in a 2Msolution of methylamine in methanol (4 mL) was heated at 150° C. in asealed tube for 48 h. The mixture was then concentrated, and the residuewas taken up in dichloromethane, washed with saturated sodiumbicarbonate aqueous solution. The organics were concentrated and theresidue was purified using reverse-phase HPLC with TFA-bufferedacetonitrile/water (40-80%) as eluent. The fractions containing theproduct were combined, neutralized with saturated sodium bicarbonateaqueous solution and lyophilized from acetonitrile/water to provide3-(4-fluorophenyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole(7-F). ¹HNMR (CDCl₃) δ 2.25-2.35 (m, 12H), 3.53 (s, 3H), 7.21 (t, J=8.7Hz, 2H), 7.54 (m, 1H), 7.73 (m, 2H), 7.88 (m, 1H), 8.13 (m, 2H). ESI-MSm/z (M+H) 498.2.

EXAMPLE 8

4-[4-Methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]-3-(trifluoromethyl)phenol(8-F)

Preparation of 4-phenylbicyclo[2.2.2]octane-1-carboxylic Acid (8-A)

Literature Reference:

-   Chapman, N. B, Sotheeswaran, S., and Toyne, K. J, J. Org. Chem, 35:    917-923 (1970)    Step A:

To a magnetically stirred solution of4-phenylbicyclo[2.2.2]octane-1-carboxylic acid (8-A) (70 mg, 0.30 mmol)in methylene chloride (1 mL) at room temperature was added 2 M oxalylchloride in methylene chloride (0.61 mL, 1.22 mmol). Two drops ofcatalytic DMF were added to catalyze the reaction. The reaction wasstirred for 30 min and solvent and reagent removed in vacuo. Methylenechloride (1 mL) was added to the residue, followed by4-(benzyloxy)-2-(trifluoromethyl)benzoic hydrazide (8-B) (141 mg, 0.46mmol) and triethylamine (0.07 mL, 0.46 mmol). The reaction was stirredat room temperature overnight to afford intermediate 8-C,N′-[4-(benzyloxy)-2-(trifluoromethyl)benzoyl]-4-phenylbicyclo[2.2.2]octane-1-carbohydrazide,which was not isolated. To the crude product (8-C) were then added2-chloro-1,3-dimethylimidazolinium chloride (257 mg, 1.52 mmol), moretriethylamine (0.42 mL, 3.04 mmol), and methylene chloride (2 mL). Thereaction was stirred at room temperature for 4 h. The reaction mixturewas then diluted with methylene chloride (30 mL) and washed with water(30 mL) two times and with brine (30 mL) once. The combined aqueouslayers were extracted with methylene chloride (25 mL) once. The combinedorganic layers were dried (MgSO₄) and the solvent removed in vacuo. Theresidue was chromatographed on silica with 10% ethyl acetate in hexanesas eluant to give2-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole(8-D). MS: m/z 505 (M+1).

Step B:

The trifluoroacetate salt of methylamine (380 mg, 2.61 mmol) and2-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole(8-D) were suspended in a 2 M solution of methylamine in methanol (1.3mL, 2.61 mmol) and heated at 150° C. overnight. After being-cooled toroom temperature, the reaction mixture was partitioned between ethylacetate (25 mL) and saturated aqueous sodium bicarbonate (30 mL). Thelayers were separated and the aqueous layer extracted with twice withethyl acetate (25 mL). The combined organic layers were washed withbrine, dried (MgSO₄), and solvent removed in vacuo. The residue was thendissolved in methanol (8 mL) and purified by reverse phasechromatography using gradient elution with 10% acetonitrile (0.1%TFA)/water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 10 min (20mL/min). The fractions containing product were partitioned betweensaturated aqueous sodium bicarbonate (25 mL) and methylene chloride (15mL). The layers were separated and the aqueous layer was extracted withmethylene chloride (15 mL) three times, dried (MgSO₄), and the solventremoved in vacuo to afford3-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)₄H-1,2,4-triazole(8-E). MS: m/z 518 (M+1).

Step C:

The3-[4-(Benzyloxy)-2-(trifluoromethyl)phenyl]-4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)₄H-1,2,4-triazole(8-E) (27 mg, 0.05 mmol) was dissolved in ethyl acetate/methanol (1:1, 4mL) to which 10% palladium-on-carbon (4 mg) was added. The reaction wasthen placed under hydrogen atmosphere and stirred for 3 h at roomtemperature and pressure. After appropriate evacuation of the hydrogenatmosphere, the palladium was filtered through a filter aid withmethanol (40 mL). The filtrate was collected and the solvent removed invacuo to afford4-[4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]-3-(trifluoromethyl)phenol(8-F). MS: m/z 428 (M+1); ¹H NMR (500 MHz, CDCl₃): δ 1.92 (6H, m), 2.11(6H, m), 3.41 (3H, s), 7.17 (2H, m), 7.24 (1H, m), 7.31 (2H, m), 7.38(3H, m) ppm.

EXAMPLE 9

3-Chloro-4-[5-(4-ethylbicyclo[2.2.2]oct-1-yl)-4-methyl-4H-1,2,4-triazol-3-yl]phenol(9-E)

Step A:

To a stirred solution of 4-ethyl-1-carboxylbicyclo[2.2.2]octane(Chapman, N. B. et al. J. Org. Chem., 1970, 35, 917) (45 mg, 0.26 mmol)in 1 mL of degassed DMF were added methylamine (2M in THF, 1 mL, 2mmol), triethylamine (0.075 mL, 0.53 mmol) and TFFH (70 mg, 0.26 mmol).The solution was stirred at room temperature for 1 h, then diluted with20 mL of ethyl acetate and washed with 1N aqueous HCl and brine. Theorganic layer was dried over anhydrous sodium sulfate and evaporated.The brown oily residue was loaded onto a flash silica gel column andeluted with a gradient ranging from 10 to 40% of ethyl acetate inhexanes. 4-Ethyl-N-methylbicyclo[2.2.2]octane-1-carboxamide (9-B) wasisolated as a clear, colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 0.80 (3H,t, J=7.2 Hz), 1.18 (2H, q, J=7.2 Hz), 1.42 (6H, m), 1.76 (6H, m), 2.81(3H,d, J=6.1 Hz).

Step B:

To a stirred solution of 9-B (45 mg, 0.23 mmol) in 0.25 mL of dry CH₂Cl₂was added oxalyl chloride (2M in CH₂Cl₂, 0.29 mL, 0.58 mmol) and 1 dropof dry DMF. The solution was stirred at room temperature for 2 h, thenevaporated. The yellow residue was redissolved in dry toluene and5-(2-chloro-4-methoxyphenyl)-2H-tetrazole (9-C) was added. The reactionmixture was heated to reflux under inert atmosphere and stirred foradditional 1.5 h before being cooled down to room temperature. The solidwas filtered, washed with toluene, then redissolved in methylenechloride and washed with saturated aqueous sodium bicarbonate and brinesolution. The organic layer was dried, then evaporated. The yellowishresidue was purified on a short plug of flash silica gel, eluting with agradient ranging from 0% to 3% of methanol in methylene chloride.3-(2-Chloro-4-methoxyphenyl)-5-(4-ethylbicyclo[2.2.2]oct-1-yl)-4-methyl-4H-1,2,4-triazole(9-D) was isolated as a white powder. MS (ESI+)=360.3 (M+1); ¹H NMR (500MHz, CDCl₃): δ 0.82 (3H, t, J=7.0 Hz), 1.22 (2H, q, J=7.0 Hz), 1.52 (6H,m), 2.10 (6H, m), 3.55 (3H,s), 3.88 (3H, s), 6.92 (1H, dd, J=8.4 Hz,J=2.8 Hz), 7.04 (1H, d, J=2.4 Hz), 7.41 (1H, d, J=8.4 Hz).

Step C:

Triazole 9-D (30 mg, 0.08 mmol) was dissolved in 0.5 mL of dry methylenechloride, placed under an inert atmosphere, and cooled to 0° C. To thissolution was added BBr₃ (1 M in CH₂Cl₂, 0.25 mL, 0.25 mmol) and thecooling bath was immediately removed. The reaction was stirred for 2 hthen diluted with 20 mL of methylene chloride and washed with 1 Naqueous NaOH and brine. The residue was chromatographed by reverse-phaseHPLC, eluting with a gradient of 0 to 100% acetonitrile in water. Theproduct,3-chloro-4-[5-(4-ethylbicyclo[2.2.2]oct-1-yl)-4-methyl-4H-1,2,4-triazol-3-yl]phenol(9-E), was isolated as a white powder. MS (ESI⁺)=346.2 (M+1); ¹H NMR(500 MHz, CDCl₃): δ 0.85 (3H, t, J=7.5 Hz), 1.25 (2H, q, J=7.5 Hz), 1.55(6H, m), 2.13 (6H, m), 3.58 (3H,s), 6.68 (1H, dd, J=8.4 Hz, J=2.6 Hz),6.91 (1H, d, J=2.6 Hz), 7.10 (1H, d, J=8.4 Hz).

EXAMPLE 10

3-{4-[2-(Ethylsulfonyl)ethyl]bicyclo[2.2.2]oct-1-yl}-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole(10-6)

Step A:

Diethyl (ethylsulfonomethane)phosphonate (1.12 g, 4.6 mmol) (Popoff, I.C. et al. J. Org. Chem. 34: 1128-30 (1969)) and4-carbomethoxybicyclo[2.2.2]octane-1-carboxaldehyde (10-1) (0.82 g, 4.2mmol) (Adcock, W., Kok, G. B. J. Org. Chem. 50: 1079-1087 (1985)) weredissolved in 8 mL of absolute methanol. The mixture was placed undernitrogen atmosphere, cooled in an ice-bath, and treated with 0.5Msolution of sodium methoxide in methanol (8.8 mL, 4.4 mmol). Thereaction mixture was kept under reflux for 4 h, then cooled to roomtemperature, concentrated under diminished pressure, then treated with 2mL of water and allowed to sit in the refrigerator overnight. Themixture was filtered and the solid washed with a small amount of cold1:1 MeOH/water. The resulting white solid was collected and dried undervacuum to give the unsaturated sulfone 10-2. MS (ESI⁺)=287 (M+1).

Step B:

Sulfone 10-2 (880 mg, 3.08 mmol) was dissolved in a 1:2 mixture of ethylacetate/methanol (30 mL), placed under nitrogen atmosphere, then treatedwith 10% Pd/C (800 mg). The reaction was placed under hydrogenatmosphere and stirred vigorously for 90 min. The resulting solution wasfiltered through celite, washed with methanol and ethyl acetate andevaporated to give methyl4-[2-(ethylsulfonyl)ethyl]bicyclo[2.2.2]octane-1-carboxylate (10-3) as awhite solid.

Step C:

Ester 10-3 (880 mg, 3 mmol) was dissolved in 10% water/methanol solution(100 mL) and treated with 1 g of potassium hydroxide. The reaction washeated at 60° C. for 1 h then at 45° C. overnight. The mixture wasconcentrated in vacuo then acidified to pH 2 with 1M HCl and extractedwith three portions of methylene chloride. The organic layers werecombined, dried over anhydrous sodium sulfate and evaporated to give4-[2-(ethylsulfonyl)ethyl]bicyclo[2.2.2]octane-1-carboxylic acid (14).

Step D:

Carboxylic acid 10-4 (810 mg, 2.96 mmol) was dissolved in 12 mL ofanhydrous methylene chloride under nitrogen atmosphere, treated withoxalyl chloride (2M in methylene chloride, 4.4 mL, 8.8 mmol) andsubsequently with 5 drops of DMF. The reaction was stirred at roomtemperature under nitrogen atmosphere for 90 min, then evaporated andplaced under vacuum for 20 min. The acid chloride was dissolved inanhydrous methylene chloride (12 mL), cooled in an ice-bath, and thentreated dropwise with a solution of methylamine (2M in THF, 8.9 mL, 17.8mmol). Upon addition of the amine, the cooling bath was removed and thereaction stirred at ambient temperature for 30 min. The mixture wasdiluted with 200 mL of methylene chloride and washed with 1N aqueousHCl, saturated aqueous sodium bicarbonate, and brine. The organic layerwas dried over anhydrous sodium sulfate and evaporated. The residue wassubjected to chromatography on silica gel eluting with a gradient from 0to 3.5% methanol in methylene chloride to give4-[2-(ethylsulfonyl)ethyl]-N-methylbicyclo[2.2.2]octane-1-carboxamide10-5 as a white powder. MS (ESI⁺)=288 (M+1).

Step E:

Methyl amide 10-5 (220 mg, 0.77 mmol) was dissolved in anhydrousmethylene chloride (2 mL) and treated with oxalyl chloride (2M inmethylene chloride, 0.77 mL, 1.54 mmol) and DMF (2 drops). The solutionwas stirred at room temperature for 1 h, then solvent removed byevaporation under diminished pressure. The residue was redissolved inanhydrous toluene (2 mL) and treated with5[2-(trifluoromethyl)phenyl]1H-tetrazole (214 mg, 1 mmol). The mixturewas refluxed for 18 h. The reaction was cooled to room temperature andthe cream-colored precipitate was filtered and washed to give 300 mg ofcrude product as the HCl salt. The salt was taken up in methylenechloride/1N HCl and the aqueous layer was washed with two additionalportions of methylene chloride. The organic layers were combined andevaporated and the residue was chromatographed by flash silica gelchromatography. Elution was carried out with a gradient ranging from 0to 5% methanol/methylene chloride. The appropriate fractions werecombined and evaporated to give3-{4-[2-(ethylsulfonyl)ethyl]bicyclo[2.2.2]oct-1-yl}-4-methyl-5-[2-(trifluoromethyl)phenyl]4H-1,2,4-triazole(10-6) as a white powder. MS (ESI⁺)=456.2 (M+1); ¹H NMR (500 MHz,CDCl₃): δ 1.46 (3H, t, J=7.3 Hz), 1.63 (6H, m), 1.78 (2H, m), 2.19 (6H,m), 2.96 (2H,m), 3.05 (2H, q, J=7.2 Hz), 3.50 (3H, s), 7.56 (1H, m),7.72 (2H, m), 7.87 (1H, m) ppm.

EXAMPLE 11

3-{4-[3-(Ethylsulfonyl)propyl]bicyclo[2.2.2]oct-1-yl}-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole(11-10)

Step A:

(Benzyloxycarbonylmethyl)triphenylphosphonium bromide (4.6 g, 9.4 mmol)was azeotroped twice from toluene, and then suspended in 30 mL dry THF.Potassium hexamethyldisilazide (0.5 M in toluene, 16.8 mL, 8.4 mmol) wasadded dropwise at room temperature and the yellow solution was allowedto stir for 1 h, after which time it became milky white. A solution of4-carbomethoxybicyclo[2.2.2]octane-1-carboxaldehyde (I) (0.50 g, 2.55mmol) (Adcock, W., Kok, G. B. J. Org. Chem. 50: 1079-1087 (1985)) andbenzoic acid (0.015 g, 0.13 mmol) in 2 mL of dry THF was prepared andadded dropwise by syringe at room temperature. The mixture was heated to90° C. and allowed to stir at reflux temperature, after which time themixture was diluted with 200 mL of ethyl acetate and washedconsecutively with 50 mL portions of 1 N HCl (twice), saturated aq.sodium bicarbonate, and brine. The organic layer was dried usingmagnesium sulfate, and the solvent was removed under reduced pressure.The residue was chromatographed on silica, eluting with a gradient of 5%to 10% ethyl acetate in hexane to provide methyl4-[(1E)-3-(benzyloxy)-3-oxoprop-1-en-1-yl]bicyclo[2.2.2]octane-1-carboxylate(11-2 as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 7.4 (5H, m), 6.94(1H, d, J=17 Hz), 5.77 (1H, d, J=17 Hz), 5.21 (2H, s), 3.69 (3H, s),1.86 (6H, m), 1.63 (6H, m) ppm.

Step B:

Diester 11-2 (0.625 g, 1.90 mmol) was dissolved in a 1:1 mixture ofethyl acetate/methanol (30 mL), placed under nitrogen atmosphere, thentreated with 10% Pd/C (500 mg) and 0.1 mL of acetic acid. The reactionwas placed under hydrogen atmosphere and stirred vigorously for 2 hr.The resulting solution was filtered through celite and the solvent wasremoved under reduced pressure. The residue was partitioned between 200mL of ethyl acetate and 200 mL of 1 N NaOH solution. The aqueous layerwas separated and neutralized, then extracted three times with 50 mL ofmethylene chloride. The combined organic layers were dried overmagnesium sulfate and the solvent was removed under reduced pressure toafford 3-[4-(methoxycarbonyl)bicyclo[2.2.2]oct-1-yl]propanoic acid(11-3). ¹H NMR (500 MHz, CDCl₃): δ 3.62 (3H, s), 2.20 (2H, broad t, J=9Hz), 1.75 (6H, m), 1.47 (2H, broad t, J=9 Hz), 1.38 (6H, m) ppm.

Step C:

Carboxylic acid 11-3 (400 mg, 1.67 mmol) was dissolved intetrahydrofuran (5 mL) and borane (1 M solution in THF, 2.17 mL, 1.3eq.) was added dropwise at room temperature. After 2 h the reaction wasadded to 50 mL of 1 N HCl and then extracted three times with 50 mL ofmethylene chloride. The combined organic layers were dried overmagnesium sulfate and the solvent was removed under reduced pressure toafford crude methyl4-(3-hydroxypropyl)bicyclo[2.2.2]octane-1-carboxylate (11-4) which wasused without purification in the next step. ¹H NMR (500 MHz, CD₃OD): δ3.66 (3H, s), 3.62 (2H, t, J=6.5 Hz), 1.78 (6H, m), 1.50 (2H, m), 1.41(2H, m), 1.17 (2H, m) ppm.

Step D:

Hydroxyester 11-4 (430 mg, 1.9 mmol) was dissolved in 2.5 mL ofanhydrous methylene chloride under nitrogen atmosphere, treated withpyridine (0.5 mL) and methanesulfonyl chloride (0.368 mL, 4.8 mmol) andstirred for 4 h at room temperature. The mixture was diluted with 100 mLof ethyl acetate and washed with 1N aqueous HCl, saturated aqueoussodium bicarbonate, and brine. The organic layer was dried overanhydrous sodium sulfate and evaporated. The crude methyl4-{3-[(methylsulfonyl)oxy]propyl}bicyclo-[2.2.2]octane-1-carboxylate(11-5) thus afforded was used without purification in the next reaction.¹H NMR (500 MHz, CDCl₃): δ 4.22 (2H, t, J=7.5 Hz), 3.68 (3H, s), 3.04(3H, s), 1.82 (6H, m), 1.70 (2H, m), 1.44 (6H, m), 1.24 (2H, m) ppm.

Step E:

Mesylate 11-5 (3.30 g, 10.9 mmol) was dissolved in DMF (20 mL) andtreated with sodium ethanethiolate (1.82 g, 21.7 mmol). The solution wasstirred at 45° C. for 3 h, then the mixture was diluted with 100 mL ofethyl acetate and washed twice with 1N aqueous HCl, then with saturatedaqueous sodium bicarbonate, and brine. The organic layer was dried overanhydrous sodium sulfate and evaporated to afford methyl4-[3-(ethylthio)propyl]bicyclo[2.2.2]octane-1-carboxylate (11-6) as acrude oil which was used without purification in the next step.

¹HNMR (500 MHz, CDCl₃): 63.68 ppm (3H, s), 2.56 (2H, q, J=7 Hz), 2.51(2H, t, J=7.5 Hz), 1.80 (6H, m), 1.52 (2H,m), 1.42 (6H, m), 1.28 (2H, t,J=7 Hz), 1.02 (2H, m).

Step F:

Sulfide 11-6 (3.0 g, 11 mmol) was dissolved in methylene chloride (50mL) and treated with m-chloroperbenzoic acid (75%, 6.2 g). The solutionwas stirred at room temperature for 2 h, then the mixture was dilutedwith 100 mL of methylene chloride and washed with saturated aqueoussodium bicarbonate, then twice with saturated aqueous sodium bisulfite,then twice with saturated aqueous sodium bicarbonate, and brine. Theorganic layer was dried over anhydrous sodium sulfate and evaporated toafford methyl4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]octane-1-carboxylate (11-7) asa crude oil which was used without purification in the next step. ¹H NMR(500 MHz, CDCl₃): δ 3.68 ppm (3H, s), 2.56 (2H, q, J=7 Hz), 2.51 (2H, t,J=7.5 Hz), 1.80 (6H, m), 1.52 (2H,m), 1.42 (6H, m), 1.28 (2H, t, J=7Hz), 1.02 (2H, m) ppm.

Step G:

Sulfone 11-7 (3.1 g, 10 mmol) was dissolved in 9:1 MeOH/water (50 mL)and treated with potassium hydroxide (3 g). The solution was stirred atroom temperature overnight, then the mixture was acidified with 1 N HCland extracted four times with 50 mL of methylene chloride. The organiclayer was dried over anhydrous sodium sulfate and evaporated to afford4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]octane-1-carboxylic acid (11-8)which was used without purification in the next step. ¹H NMR (500 MHz,CDCl₃): δ 3.03 (2H, q, J=7 Hz), 2.94 (2H, dd, J=7.5 Hz), 1.84 (8H, m),1.45 (8H,m), 1.30 (2H, m) ppm.

Step H:

Carboxylic acid 11-8 (3.0 g, 11 mmol) was dissolved in 50 mL ofanhydrous methylene chloride under nitrogen atmosphere, treated withoxalyl chloride (2 M in methylene chloride, 16.2 mL, 32.4 mmol) andsubsequently with 5 drops of DMF. The reaction was stirred at roomtemperature under nitrogen atmosphere for 90 min, then evaporated andplaced under vacuum for 20 min. The acid chloride was dissolved inanhydrous methylene chloride (12 mL), cooled in an ice-bath, and thentreated dropwise with a solution of methylamine (2M in THF, 27 mL, 54mmol). Upon addition of the methylamine, the cooling bath was removedand the reaction stirred at ambient temperature for 30 min. The mixturewas diluted with 200 mL of methylene chloride and washed with 1N aqueousHCl, saturated aqueous sodium bicarbonate, and brine. The organic layerwas dried over anhydrous sodium sulfate and evaporated. The residue wassubjected to chromatography on silica gel eluting with a gradient from 0to 3% methanol in ethyl acetate to give4-[3-(ethylsulfonyl)propyl]-N-methylbicyclo[2.2.2]octane-1-carboxamide11-9 as a white powder. MS (ESI⁺)=302 (M+1). ¹H NMR (500 MHz, CDCl₃): δ5.56 (1H, br s), 3.02 (2H, q, J=7 Hz), 2.94 (2H, dd, J=7.5 Hz), 2.82(3H, d, J=4 Hz), 1.80 (8H,m), 1.45 (9H, m), 1.28 (2H, m) ppm.

Step I:

Methyl amide 11-9 (0.470 g, 1.56 mmol) was dissolved in anhydrousmethylene chloride (5 mL) and treated with oxalyl chloride (2M inmethylene chloride, 1.56 mL, 3.12 mmol) and DMF (2 drops). The solutionwas stirred at room temperature for 1 h, then solvent removed byevaporation under reduced pressure. The residue was redissolved inanhydrous toluene (7 mL) and treated with5[2-(trifluoromethyl)phenyl]1H-tetrazole (368 mg, 1.72 mmol). Themixture was refluxed for 18 h. The reaction was cooled to roomtemperature and the precipitate was filtered and washed to give 300 mgof crude product as the HCl salt. The salt was taken up in methylenechloride/1N HCl and the aqueous layer was washed with two additionalportions of methylene chloride. The organic layers were combined andevaporated and the residue was chromatographed by flash silica gelchromatography. Elution was carried out with a gradient ranging from 0to 5% methanol/methylene chloride. The appropriate fractions werecombined and evaporated to give3-{4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]oct-1-yl}4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole(11-10) as a white powder. MS (ESI⁺)=470.4 (M+1). ¹H NMR (500 MHz,CDCl₃): δ 7.87 (1H, m), 7.72 (2H, m), 7.56 (1H, m), 3.49 (3H, s), 3.05(2H, q, J=7.2 Hz), 2.96 (2H,m), 2.18 (6H, m), 1.86 (2H, m), 1.62 (6H,m), 1.46 (3H, t, J=7.3 Hz), 1.36 (2H, m) ppm.

EXAMPLE 12

4-Methyl-3-{4-[4-(methylsulfonyl)phenyl]bicyclo[2.2.2]oct-1-yl}-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole(12-G)

Step A:

To a stirred solution of methyl4-phenylbicyclo[2.2.2]octane-1-carboxylate 12-A (Chapman, N. B. et al.J. Org. Chem., 1970, 35, 917) (4.80 g, 19.6 mmol) in 1,2-dichloroethane(2 ml, 1M) was added methanesulfonyl fluoride (4.05 ml, 58.9 mmol)followed by aluminum trichloride (9.17 g, 68.8 mmol). The reactionmixture was stirred overnight under nitrogen atmosphere at ambienttemperature followed by addition of another portion of methanesulfonylfluoride (4.05 ml, 58.9 mmol) and aluminum trichloride (9.17 g, 68.8mmol). The resulting mixture was heated at 80° C. for 3 h, then cooledto room temperature and diluted with 300 ml of dichloromethane and 200ml water. The layers were separated and the aqueous layer was washedwith two 100 ml portions of dichloromethane. The organic layers werecombined, washed with brine, dried (MgSO₄), and concentrated in vacuo.The crude product was chromatographed on normal phase flash silica gelcolumn, eluting with a gradient 10-50% EtOAc/hexanes to yield 1.4 g of12-B (>95% pure). The material was recrystallized from EtOAc to yieldcompound 12-B. ¹H NMR (500 MHz, CDCl₃): δ 1.93 (6H, m), 1.99 (6H, m),3.08 (3H, s), 3.73 (3H, s), 7.55 (2H, d, J=8.3 Hz), 7.90(2H, d, J=8.1Hz) ppm.

Step B:

Carboxylic acid 12-C was prepared in quantitative yield by hydrolysis ofester 12-B (1.1 g, 3.4 mmol) using the procedures described in Example11, Step G. ¹H NMR (500 MHz, CDCl₃): δ 1.98 (6H, m), 2.04 (6H, m), 3.11(3H, s), 7.58 (2H, d, J=7.8 Hz), 7.92 (2H, d, J=7.9 Hz) ppm.

Step C:

Carboxylic acid 12-C (0.99 g, 3.2 mmol) was converted to hydrazide 12-Dusing hydrazine (0.124 ml, 0.4 mmol) and the standard coupling procedureanalogous to Example 9, step A. Crude product was purified by flashsilica gel chromatography eluting with 0-2% MeOH/CH₂Cl₂ gradient toyield a white powder. MS (ESI⁺)=323.2 (M+1).

Step D:

To a suspension of 12-D (0.67 g, 2.1 mmol) in EtOH (11 ml) was addedaldehyde 12-E (0.36 g, 2.1 mmol) and the mixture was refluxed for 18 h.The solvent was removed in vacuo and the solid residue was heated inthionyl chloride (2.9 ml, 40 mmol) for 2 h at 75° C. then stripped todryness. This residue was treated with methylamine (2M THF, 2 ml) andmethylamine (40% aqueous, 1 ml) for 18 h at 70° C. The volatiles wereremoved in vacuo and the solid was chromatographed on a flash silica gelcolumn using a 10-25% acetone/hexanes gradient to yield compound 12-F.MS (ESI⁺)=492.3 (M+1);

¹H NMR (500 MHz, CDCl₃) (2 isomers ratio 3:2): major isomer: δ 2.00 (6H,m), 2.14 (6H, m), 3.10 (3H, s), 3.28 (3H, d, J=5.1 Hz), 5.71 (1H, br.s), 7.47 (1H, m), 7.59 (3H, m), 7.72 (1H, d, J=7.9 Hz), 7.92 (2H, m),8.26 (1H, d, J=7.9 Hz), 8.70 (1H, br. s) ppm; minor isomer: δ 2.00 (6H,m), 2.32 (6H, m), 2.98 (3H, d, J=4.7 Hz), 3.10 (3H, s), 4.70 (1H, br.s), 7.47 (1H, m), 7.59 (4H, m), 7.92 (2H, m), 8.30 (1H, d, J=7.8 Hz),8.56 (1H, br. s) ppm.

Step E:

A solution of 12-F (0.58 g, 1.2 mmol) in EtOH (5 ml) was heated to 40°C. then treated with a solution of ferric chloride (0.4 g, 2.4 mmol) inwater (1 ml). The resulting mixture was heated at 90° C. for 18 h.Another portion of ferric chloride (0.4 g, 2.4 mmol) was added and thereaction heated at 90° C. for 24 h. The volatiles were removed in vacuoand the solid was redissolved in CH₂Cl₂ and washed with a saturatedaqueous solution of EDTA and brine then dried (MgSO₄) and stripped. Thecrude product was purified and isolated using the conditions describedfor purification of 4-J (Example 4, step G) to yield compound 12-G.

MS (ESI⁺)=490.3 (M+1); ¹H NMR (500 MHz, CDCl₃): δ 2.06 (6H, m), 2.31(6H, m), 3.08 (3H, s), 3.52 (3H, s), 7.52 (1H, m), 7.59 (2H, d, J=8.4Hz), 7.71 (2H, m), 7.86 (1H, m), 7.92 (2H, d, J=8.6 Hz) ppm.

EXAMPLE 13

3-(4-{4-Methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-5-(3,3,3-trifluoropropyl)-1,2,4-oxadiazole(13-F)

Step A:

4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 13-A (Chapman,N. B. et al. J. Org. Chem., 1970, 35, 917) (4.0 g, 18.9 mmol) wasconverted to methyl4-[(methylamino)carbonyl]bicyclo[2.2.2]octane-1-carboxylate 13-B usingthe methods described in Example 10, steps C and D. Product was purifiedby flash silica gel chromatography, eluting with 0-5% MeOH/CH₂Cl₂gradient to yield a white solid. MS (ESI⁺)=226.2 (M+1).

Step B:

Methyl 4-[(methylamino)carbonyl]bicyclo[2.2.2]octane-1-carboxylate 13-B(2.76 g, 12.3 mmol) was converted to 1,2,4-triazole 13-C using theprocedures described in Example 10, Step E. The product, whichprecipitated out of reaction mixture as the HCl salt, was dissolved inCH₂Cl₂, washed twice with saturated aqueous sodium bicarbonate solution,dried (MgSO₄) and stripped to yield a white solid. MS (ESI⁺)=394.2(M+1);

¹H NMR (500 MHz, CDCl₃): δ 2.00 (6H, m), 2.18 (6H, m), 3.48 (3H, s),3.72 (3H, s), 7.51 (1H, m), 7.71 (2H, m), 7.85 (1H, m) ppm.

Step C:

A solution of methyl ester 13-C (1.19 g, 3.0 mmol) in 5% H₂O/MeOH (30ml) was treated with KOH (0.51 g, 9.0 mmol) at 60° C. under nitrogenatmosphere for 18 h. The resulting mixture was concentrated down,diluted with water (150 ml), washed with EtOAc and acidified withaqueous HCl (1 N) to pH=3. The precipitate was filtered, washed with asmall amount of water and ether and dried under vacuum to yield a pinksolid (0.87 g, 76%). A portion of the solid (0.67 g, 1.77 mmol) wassuspended in CH₂Cl₂ (15 ml) and treated with carbonyldiimidazole (0.57g, 3.54 mmol) at room temperature and nitrogen atmosphere. After 2 h,concentrated ammonium hydroxide was added (40 ml) and the reaction wasstirred for 18 h. The crude mixture was diluted with water (150 ml) andextracted with 3 portions of CH₂Cl₂ (70 ml). The organic washes werecombined, washed with brine, dried (Na₂SO₄), and stripped to yieldcompound 13-D as a white powder. MS (ESI⁺)=379.3 (M+1).

Step D:

A solution of carboxamide 13-D (0.64 g, 1.7 mmol) and cyanuric chloride(0.47 g, 2.53 mmol) in DMF (15 ml) was stirred at room temperature undernitrogen atmosphere. After 2 h, DMF was removed in vacuo and the solidwas redissolved in CH₂Cl₂ (100 ml) and washed with saturated aqueoussodium bicarbonate and brine, dried (Na₂SO₄), and stripped to give thenitrile 13-E as a pale yellow solid. MS (ESI⁺)=361.3 (M+1); ¹H NMR (500MHz, CDCl₃): δ 2.15 (6H, m), 2.22 (6H, m), 3.47 (3H, s), 7.51 (1H, m),7.72 (2H, m), 7.87 (1H, m) ppm.

Step E:

A solution of nitrile 13-E (0.56 g, 1.6 mmol) and hydroxylamine (50%aqueous, 4 ml) in ethanol (40 ml) was heated at 80° C. for 18 h. Theresulting mixture was cooled to room temperature and concentrated invacuo. The solid was suspended in toluene, the solvent removed in vacuo,and the solid was dried under reduced pressure. A portion of theresulting white powder (0.050 g, 0.13 mmol) was added to a pre-stirredsolution of 4,4,4-trifluorobutyric acid (0.072 g, 0.51 mmol) andcarbonyldiimidazole (0.082 g, 0.51 mmol) in CH₂Cl₂ (3 ml). The resultingmixture was stirred at room temperature for 48 h, then concentrateddown. The solid was resuspended in toluene and refluxed under nitrogenatmosphere for 3 h. The crude product was purified and isolated usingthe conditions described for purification of 4-J (Example 4, step G) toyield 13-F as a white powder.

MS (ESI⁺)=500.2 (M+1); ¹H NMR (500 MHz, CDCl₃): δ 2.12 (6H, m), 2.30(6H, m), 2.73 (2H, m), 3.18 (2H, m), 3.54 (3H, s), 7.61 (1H, m), 7.74(2H, m), 7.87 (1H, m) ppm.

EXAMPLE 14

3-(4-{4-Methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-5-(3,3,3-trifluoroethyl)-1,2,4-oxadiazole(14-B)

Step A:

Triazole 14-B was prepared from nitrile 13-E (0.053 g, 0.14 mmol) and3,3,3-trifluoromethylpropionic acid (0.036 ml, 0.41 mmol) using themethod described in Example 13, step E.3-(4-{4-Methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-5-(3,3,3-trifluoroethyl)-1,2,4-oxadiazole (14-B)was isolated as a white powder. MS (ESI+)=486.2 (M+1); ¹H NMR (500 MHz,CDCl₃): δ 2.14 (6H, m), 2.31 (6H, m), 3.53 (3H, s), 3.81 (2H, q, J=9.5Hz), 7.57 (1H, m), 7.73 (2H, m), 7.87 (1H, m) ppm.

EXAMPLE 15

4-Methyl-3-[2-(trifluoromethyl)phenyl]-5-(4-{2-[(trifluoromethyl)sulfonyl]ethyl}bicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole(15-G)

Step A:

To a stirred solution of methyltriphenylphosphonium bromide (9.1 g, 12.8mmol) in THF (50 ml) at 0° C. was added potassium hexamethyldisilazide(0.5M in toluene, 48.6 ml), dropwise over 5 min. The resulting mixturewas allowed to warm up to room temperature over 1 h, then cooled againto 0° C. and treated with methyl4-formylbicyclo[2.2.2]octane-1-carboxylate 15-A (Chapman, N. B. et al.J. Org. Chem., 1970, 35, 917) (2.5 g, 12.8 mmol). The reaction mixturewas stirred at room temperature for 18 h then diluted with EtOAc (350ml). The organic phase was washed with aqueous HCl (1 N), saturatedaqueous sodium bicarbonate, and brine, then dried (Na₂SO₄) andconcentrated in vacuo. The resulting solid was purified by flash silicagel chromatography, eluting with a gradient 0-4% EtOAc/hexanes. Theresulting methyl 4-vinylbicyclo[2.2.2]octane-1-carboxylate 15-B wasisolated as a clear, colorless oil.

Step B:

To a stirred solution of olefin 15-B (1.6 g, 8.3 mmol) in THF (20 ml)was added 9-BBN (0.5M in THF, 49 ml), dropwise. The solution was allowedto stir at room temperature for 18 h, then treated sequentially withethanol (14.5 ml), aqueous NaOH (5N, 5 ml), and hydrogen peroxide (30%aqueous, 9.7 ml). The reaction mixture was acidified to pH=2 withaqueous HCl (1 N) and extracted three times with CH₂Cl₂. The organiclayers were combined, washed with brine, dried (Na₂SO₄), and stripped.The resulting alcohol 15-C was purified by silica gel chromatographyeluting with a gradient 30-50% EtOAc/hexanes and isolated as a clear,colorless oil.

Step C:

A solution of alcohol 15-C (1.5 g, 7.1 mmol) in CH₂Cl₂ (7.5 ml),pyridine (1.5 ml) was cooled to 0° C. and treated with methanesulfonylchloride (1.65 ml, 21.3 mmol), dropwise over 5 min. The reaction mixturewas allowed to warm to room temperature, then stirred for 3 h. EtOAc(300 ml) was added and the organic phase was washed with aqueous HCl (1N) three times, saturated aqueous sodium bicarbonate two times, andbrine. The organic layer was dried (Na₂SO₄), and stripped to yieldmethyl4-{2-[(methylsulfonyl)oxy]ethyl}bicyclo[2.2.2]octane-1-carboxylate 15-Das a white solid. ¹H NMR (500 MHz, CDCl₃): δ 1.52 (6H, m), 1.66 (2H, t,J=7.1 Hz), 1.84 (6H, m), 3.04 (3H, s), 3.69 (3H, s), 4.29 (2H, t, J=7.2Hz) ppm.

Step D:

A solution of 15-D (0.25 g, 0.86 mmol), potassiumtrifluoromethanesulfinate (0.3 g, 1.72 mmol), and tetrabutylammoniumiodide (0.15 g, 0.4 mmol) in DMF (5 ml) was heated at 140° C. for 5 h.under nitrogen atmosphere. The solution was then cooled to roomtemperature and diluted with EtOAc (100 ml) and washed with aqueous HCl(1N) two times and brine. The organic layer was dried (Na₂SO₄),stripped, and chromatographed on flash silica gel, eluting with agradient 5-20% EtOAc/hexanes. The resulting trifluoromethylsulfone 15-Ewas isolated as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 1.50 (6H, m),1.78 (2H, m), 1.82 (6H, m), 3.17 (2H, m), 3.67 (3H, s) ppm.

Step E:

Methyl ester 15-E (0.035 g, 0.11 mmol) was converted to the methyl amide15-F using the methods described in Example 10, steps C and D. TheN-methyl-4-{2-[(trifluoromethyl)sulfonyl]ethyl}bicyclo[2.2.2]octane-1-carboxamidewas isolated as a white solid; MS (ESI⁺)=328.2 (M+1).

Step F:

Methyl amide 15-F (0.030 g, 0.092 mmol) was converted to triazole 15-Gusing the procedures outlined in Example 10, step E.4-Methyl-3-[2-(trifluoromethyl)phenyl]-5-(4-{2-[(trifluoromethyl)sulfonyl]ethyl}bicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole(15-G) was isolated as a white powder; MS (ESI⁺)=496.4 (M+1).

EXAMPLES 16-150

Following procedures similar to those described above, the followingcompounds of formula II were also prepared: (II)

Parent Ion Ex. # R³ R² R¹ m/z 16

CH₃

338 17

CH₃

406 18

CH₃

352 19

CH₃

372 20

CH₃

356 21

CH₃

368 22

CH₃

384 23

CH₃

383 24

CH₃

416 25

CH₃

422 26

CH₃

354 27

CH₃

382 28

CH₃

422 29

CH₃

368 30

CH₃

354 31

CH₃

496 32

CH₃

417 33

CH₃

372 34

CH₃

372 35

CH₃

352 36

CH₃

398 37

CH₃

382 38

CH₃

400 39

CH₃

368 40

CH₃

356 41

CH₃

366 42

CH₃

398 43

CH₃

374 44

CH₃

404 45

CH₃

374 46

CH₃

372 47

CH₃

372 48

CH₃

378 49

CH₃

402 50

CH₃

436 51

CH₃

370 52

CH₃

422 53

CH₃

366 54

CH₃

431 55

CH₃

382 56

CH₃

430 57

CH₃

414 58

CH₃

418 59

CH₃

474 60

CH₃

430 61

CH₃

353 62

CH₃

363 63

CH₃

366 64

CH₃

339 65

CH₃

339 66

CH₃

339 67

CH₃

355 68

CH₃

340 69

CH₃

388 70

CH₃

388 71

CH₃

378 72

CH₃

377 73

CH₃

389 74

CH₃

377 75

CH₃

380 76

CH₃

380 77

CH₃

382 78

CH₃

378 79

CH₂CH₃

382 80

CH₂CH₃

382 81

CH₂CH₃

352 82

CH₂CH₃

368 83

CH₂CH₃

380 84

CH₂CH₃

366 85

364 86

CH₃

373 87

CH₃

389 88

365 89

CH₃

340 90

CH₃

378 91

CH₃

345 92

CH₃

340 93

CH₃

326 94

CH₃

354 95

CH₃

361 96

CH₃

356 97

CH₃

340 98

CH₃

343 99

CH₃

338 100

CH₃

364 101

CH₃

326 102

CH₃

312 103

CH₃

331 104

CH₃

342 105

CH₃

326 106

CH₃

340 107

CH₃

361 108

CH₃

356 109

CH₃

365 110

CH₃

382 111

CH₃

358 112

CH₃

OMe 113

CH₃

407 114

CH₃

438 115 CH₃ CH₃

282 116

CH₃

348 117 H CH₃

284 118 H CH₃

298 119 H CH₃

302 120 H CH₃

298 121 H CH₃

336 122

CH₃

344 123

CH₃

374 124

CH₃

358 125

CH₃

360 126

CH₃

471 127

CH₃

456 128

CH₃

326 129 CbzNH— CH₃

428 130 NH₂ CH₃

313 131

CH₃

450 132

CH₃

421 133

CH₃

422 134

CH₃

402 135

CH₃

456 136

CH₃

470 137

CH₃

442 138

CH₃

440 139

CH₃

470 140

CH₃

484 141

CH₃

490 142

CH₃

508 143

CH₃

420

Furthermore following procedure similar to those described above, thefollowing compounds of formula III were also prepared: (III)

Parent Ion Ex. # R⁵ R¹ m/z 144 Cl

477 145 Cl

515 146 Cl

480 147 Cl

511 148 Cl

497 149 F

476

EXAMPLE OF A PHARMACEUTICAL FORMULATION

As a specific embodiment of an oral composition of a compound of thepresent invention, 50 mg of any of Examples 1-15 is formulated withsufficient finely divided lactose to provide a total amount of 580 to590 mg to fill a size O hard gelatin capsule.

While the invention has been described and illustrated in reference tospecific embodiments thereof, those skilled in the art will appreciatethat various changes, modifications, and substitutions can be madetherein without departing from the spirit and scope of the invention.For example, effective dosages other than the preferred doses as setforth hereinabove may be applicable as a consequence of variations inthe responsiveness of the human being treated for a particularcondition. Likewise, the pharmacologic response observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended therefore that the invention be limited only by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A method of treating neurodegenerative disease in a mammalian patientcomprising administering to the patient an effective amount of acompound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein each p isindependently 0, 1, or 2; each n is independently 0, 1, or 2; X isselected from the group consisting of a single bond, O, S(O)_(p), NR⁶,

R¹ is selected from the group consisting of arylcarbonyl,(CH₂)_(n)-aryl, and (CH₂)_(n)-heteroaryl; in which aryl and heteroarylare unsubstituted or substituted with one to three substituentsindependently selected from R⁵; R² is selected from the group consistingof hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, and (CH₂)_(n)—C₃₋₆ cycloalkyl; inwhich alkyl, alkenyl, and cycloalkyl are unsubstituted or substitutedwith one to three substituents independently selected from R⁸ and oxo;each R⁴ is independently selected from the group consisting of hydrogen,halogen, hydroxy, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; R³ is selected fromthe group consisting of hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,(CH₂)_(n)—C₃₋₆ cycloalkyl, (CH₂)_(n)-aryl, and (CH₂)_(n)-heteroaryl;(CH₂)_(n)-heterocyclyl; in which aryl, heteroaryl and heterocyclyl areunsubstituted or substituted with one to three substituentsindependently selected from R⁵; and alkyl, alkenyl, and cycloalkyl areunsubstituted or substituted with one to five groups independentlyselected from R⁸ and oxo; R⁵ and R⁸ are independently selected from thegroup consisting of hydrogen, formyl, C₁₋₆ alkyl, (CH₂)_(n)-aryl,(CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl,halogen, OR⁷, (CH₂)_(n)N(R⁷)₂, cyano, (CH₂)_(n)CO₂R⁷, NO₂,(CH₂)_(n)NR⁷SO₂R⁶, (CH₂)_(n)SO₂N(R⁷)₂, (CH₂)_(n)S(O)_(p)R⁶,(CH₂)_(n)SO₂OR⁷, (CH₂)_(n)NR⁷C(O)N(R⁷)₂, (CH₂)_(n)C(O)N(R⁷)₂,(CH₂)_(n)NR⁶C(O)R⁶, (CH₂)_(n)NR⁶CO₂R⁷, O(CH₂)_(n)C(O)N(R⁷)₂, CF₃,CH₂CF₃, OCF₃, OCHCF₂, and OCH₂CF₃; wherein aryl, heteroaryl, cycloalkyl,and heterocyclyl are unsubstituted or substituted with one to threesubstituents independently selected from halogen, hydroxy, C₁₋₄ alkyl,trifluoromethyl, trifluoromethoxy, and C₁₋₄ alkoxy; and wherein anymethylene (CH₂) carbon atom in R⁵ and R⁸ is unsubstituted or substitutedwith one to two groups independently selected from halogen, hydroxy, andC₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) carbonatom are taken together with the carbon atom to which they are attachedto form a cyclopropyl group; each R⁶ is independently selected from thegroup consisting of C₁₋₈ alkyl, (CH₂)_(n)-aryl, (CH₂)_(n)-heteroaryl,and (CH₂)_(n)C₃₋₇ cycloalkyl; wherein alkyl and cycloalkyl areunsubstituted or substituted with one to five substituents independentlyselected from halogen, oxo, C₁₋₄ alkoxy, C₁₋₄ alkylthio, hydroxy, amino;and aryl and heteroaryl are unsubstituted or substituted with one tothree substituents independently selected from cyano, halogen, hydroxy,amino, carboxy, trifluoromethyl, trifluoromethoxy, C₁₋₄ alkyl, and C₁₋₄alkoxy; or two R⁶ groups together with the atom to which they areattached form a 5- to 8-membered mono- or bicyclic ring systemoptionally containing an additional heteroatom selected from O, S, andNC₁₋₄ alkyl; and each R⁷ is hydrogen or R⁶. 2-19. (canceled)
 20. Amethod in accordance with claim 1 wherein the compound administered is acompound of structural formula II selected from the group consisting of:(II)

R³ R² R¹

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₂CH₃

CH₂CH₃

CH₂CH₃

CH₂CH₃

CH₂CH₃

CH₂CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃ CH₃

CH₃

H CH₃

H CH₃

H CH₃

H CH₃

H CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CbzNH— CH₃

NH₂ CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

CH₃

or a pharmaceutically acceptable salt thereof.
 21. A method inaccordance with claim 1 wherein the compound administered is a compoundof structural formula III selected from the group consisting of: (III)

R⁵ R¹ Cl

Cl

Cl

Cl

Cl

F

F

F

or a pharmaceutically acceptable salt thereof.
 22. A method inaccordance with claim 20 wherein the compound administered is selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.
 23. A method inaccordance with claim 21 wherein the compound administered is

or a pharmaceutically acceptable salt thereof.
 24. A method inaccordance with claim 22 wherein the compound administered is

or a pharmaceutically acceptable salt thereof.
 25. A method inaccordance with claim 22 wherein the compound administered is

or a pharmaceutically acceptable salt thereof.
 26. A method inaccordance with claim 22 wherein the compound administered is

or a pharmaceutically acceptable salt thereof.
 27. A method inaccordance with claim 22 wherein the compound administered is

or a pharmaceutically acceptable salt thereof. 28-35. (canceled)
 36. Amethod of delaying the onset of a neurodegenerative disease in a patientin need thereof, comprising administering to the patient a compound ofthe formula I:

or a pharmaceutically acceptable salt thereof, wherein each p isindependently 0, 1, or 2; each n is independently 0, 1, or 2; X isselected from the group consisting of a single bond, O, S(O)_(p), NR⁶,

R¹ is selected from the group consisting of arylcarbonyl,(CH₂)_(n)-aryl, and (CH₂)_(n)-heteroaryl in which aryl and heteroarylare unsubstituted or substituted with one to three substituentsindependently selected from R⁵; R² is selected from the group consistingof hydrogen, C₁₋₈ alkyl C₂₋₆ alkenyl, and (CH₂)_(n)—C₃₋₆ cycloalkyl; inwhich alkyl, alkenyl, and cycloalkyl are unsubstituted or substitutedwith one to three substituents independently selected from R⁸ and oxo;each R⁴ is independently selected from the group consisting of hydrogen,halogen, hydroxy, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; R³ is selected fromthe group consisting of hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,(CH₂)_(n)—C₃₋₆ cycloalkyl, (CH₂)_(n)-aryl, and (CH₂)_(n)-heteroaryl;(CH₂)_(n)-heterocyclyl; in which aryl, heteroaryl and heterocyclyl areunsubstituted or substituted with one to three substituentsindependently selected from R⁵; and alkyl, alkenyl, and cycloalkyl areunsubstituted or substituted with one to five groups independentlyselected from R⁸ and oxo; R⁵ and R⁸ are independently selected from thegroup consisting of hydrogen, formyl, C₁₋₆ alkyl (CH₂)_(n)-aryl,(CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl,halogen, OR⁷, (CH₂)_(n)N(R⁷)₂, cyano, (CH₂)_(n)CO₂R⁷, NO₂,(CH₂)_(n)NR⁷SO₂R⁶, (CH₂)_(n)SO₂N(R⁷)₂, (CH₂)_(n)S(O)_(p)R⁶,(CH₂)_(n)SO₂OR⁷, (CH₂)_(n)NR⁷C(O)N(R⁷)₂, (CH₂)_(n)C(O)N(R⁷)₂,(CH₂)_(n)NR⁶C(O)R⁶, (CH₂)_(n)NR⁶CO₂R⁷, O(CH₂)_(n)C(O)N(R⁷)₂, CF₃,CH₂CF₃, OCF₃, OCHCF₂, and OCH₂CF₃; wherein aryl, heteroaryl, cycloalkyl,and heterocyclyl are unsubstituted or substituted with one to threesubstituents independently selected from halogen, hydroxy, C₁₋₄ alkyl,trifluoromethyl, trifluoromethoxy, and C₁₋₄ alkoxy; and wherein anymethylene (CH₂) carbon atom in R⁵ and R⁸ is unsubstituted or substitutedwith one to two groups independently selected from halogen, hydroxy, andC₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) carbonatom are taken together with the carbon atom to which they are attachedto form a cyclopropyl group; each R⁶ is independently selected from thegroup consisting of C₁₋₈ alkyl. (CH₂)_(n)-heteroaryl, and (CH₂)_(n)C₃₋₇cycloalkyl; wherein alkyl and cycloalkyl are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, oxo, C₁₋₄ alkoxy, C₁₋₄ alkylthio, hydroxy, amino; and aryl andheteroaryl are unsubstituted or substituted with one to threesubstituents independently selected from cyano, halogen, hydroxy, amino,carboxy, trifluoromethyl, trifluoromethoxy, C₁₋₄ alkyl, and C₁₋₄ alkoxy;or two R⁶ groups together with the atom to which they are attached forma 5- to 8-membered mono- or bicyclic ring system optionally containingan additional heteroatom selected from O, S, and NC₁₋₄ alkyl; and eachR⁷ is hydrogen or R⁶, in an amount that is effective to delay the onsetof said condition.
 37. A method of reducing the risk of developing aneurodegenerative disease in a mammalian patient in need thereof,comprising administering to the patient a compound represented byformula I:

or a pharmaceutically acceptable salt thereof; wherein each p isindependently 0, 1, or 2; each n is independently 0, 1, or 2; X isselected from the group consisting of a single bond, O, S(O)_(p), NR⁶,

R¹ is selected from the group consisting of arylcarbonyl.(CH₂)_(n)-aryl, and (CH₂)_(n)-heteroaryl; in which aryl and heteroarylare unsubstituted or substituted with one to three substituentsindependently selected from R⁵; R² is selected from the group consistingof hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, and (CH₂)_(n)—C₃₋₆ cycloalkyl; inwhich alkyl, alkenyl, and cycloalkyl are unsubstituted or substitutedwith one to three substituents independently selected from R⁸ and oxo;each R⁴ is independently selected from the group consisting of hydrogen,halogen, hydroxy, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; R³ is selected fromthe group consisting of hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,(CH₂)_(n)—C₃₋₆ cycloalkyl, (CH₂)_(n)-aryl; and (CH₂)_(n)-heteroaryl;(CH₂)_(n)-heterocyclyl; in which aryl, heteroaryl and heterocyclyl areunsubstituted or substituted with one to three substituentsindependently selected from R⁵; and alkyl, alkenyl, and cycloalkyl areunsubstituted or substituted with one to five groups independentlyselected from R⁸ and oxo; R⁵ and R⁸ are independently selected from thegroup consisting of hydrogen, formyl, C₁₋₆ alkyl, (CH₂)_(n)-aryl,(CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl,halogen, OR⁷, (CH₂)_(n)N(R⁷)₂, cyano (CH₂)_(n)CO₂R⁷, NO₂,(CH₂)_(n)NR⁷SO₂R⁶, (CH₂)_(n)SO₂N(R⁷)₂, (CH₂)_(n)S(O)_(p)R⁶,(CH₂)_(n)SO₂OR⁷, (CH₂)_(n)NR⁷C(O)N(R⁷)₂, (CH₂)_(n)C(O)N(R⁷)₂,(CH₂)_(n)NR⁶C(O)R⁶, (CH₂)_(n)NR⁶CO₂R⁷, O(CH₂)_(n)C(O)N(R⁷)₂, CF₃,CH₂CF₃, OCF₃, OCHCF₂, and OCH₂CF₃; wherein aryl, heteroaryl, cycloalkyl,and heterocyclyl are unsubstituted or substituted with one to threesubstituents independently selected from halogen, hydroxy, C₁₋₄ alkyl,trifluoromethyl, trifluoromethoxy, and C₁₋₄ alkoxy; and wherein anymethylene (CH₂) carbon atom in R⁵ and R⁸ is unsubstituted or substitutedwith one to two groups independently selected from halogen, hydroxy, andC₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) carbonatom are taken together with the carbon atom to which they are attachedto form a cyclopropyl group; each R⁶ is independently selected from thegroup consisting of C₁₋₈ alkyl, (CH₂)_(n)-aryl, (CH₂)_(n)-heteroaryl,and (CH₂)_(n)C₃₋₇ cycloalkyl: wherein alkyl and cycloalkyl areunsubstituted or substituted with one to five substituents independentlyselected from halogen, oxo, C₁₋₄ alkoxy, C₁₋₄ alkylthio, hydroxy, amino;and aryl and heteroaryl are unsubstituted or substituted with one tothree substituents independently selected from cyano, halogen, hydroxy,amino, carboxy, trifluoromethyl, trifluoromethoxy, C₁₋₄ alkyl, and C₁₋₄alkoxy; or two R⁶ groups together with the atom to which they areattached form a 5- to 8-membered mono- or bicyclic ring systemoptionally containing an additional heteroatom selected from O, S, andNC₁₋₄ alkyl; and each R⁷ is hydrogen or R⁶ in an amount that iseffective to reduce the risk of developing said condition.
 38. A methodof treating neurodegenerative disease in a mammalian patient in need ofsuch treatment, comprising administering to the patient a compound offormula I:

or a pharmaceutically acceptable salt thereof; wherein each p isindependently 0, 1, or 2; each n is independently 0, 1, or 2; X isselected from the group consisting of a single bond, O, S(O)_(p), NR⁶,

R¹ is selected from the group consisting of arylcarbonyl,(CH₂)_(n)-aryl, and (CH₂)_(n)-heteroaryl; in which aryl and heteroarylare unsubstituted or substituted with one to three substituentsindependently selected from R⁵, R² is selected from the group consistingof hydrogen, C_(1-8 alkyl,) C₂₋₆ alkenyl, and (CH₂)_(n)—C₃₋₆ cycloalkyl;in which alkyl, alkenyl, and cycloalkyl are unsubstituted or substitutedwith one to three substituents independently selected from R⁸ and oxo;each R⁴ is independently selected from the group consisting of hydrogen,halogen, hydroxy, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; R³ is selected fromthe group consisting of hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,(CH₂)_(n)—C₃₋₆ cycloalkyl, (CH₂)_(n)-aryl, and (CH₂)_(n)-heteroaryl;(CH₂)_(n)-heterocyclyl; in which aryl, heteroaryl and heterocyclyl areunsubstituted or substituted with one to three substituentsindependently selected from R⁵; and alkyl, alkenyl, and cycloalkyl areunsubstituted or substituted with one to five groups independentlyselected from R⁸ and oxo; R⁵ and R⁸ are independently selected from thegroup consisting of hydrogen, formyl, C₁₋₆ alkyl, (CH₂)_(n)-aryl,(CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl,halogen, OR⁷, (CH₂)_(n)N(R⁷)₂, cyano, (CH₂)_(n)CO₂R⁷, NO₂,(CH₂)_(n)NR⁷SO₂R⁶, (CH₂)_(n)SO₂N(R⁷)₂, (CH₂)_(n)S(O)_(p)R⁶,(CH₂)_(n)SO₂OR⁷, (CH₂)_(n)NR⁷C(O)N(R⁷)₂, (CH₂)_(n)C(O)N(R⁷)²,(CH₂)_(n)NR⁶C(O)R⁶, (CH₂)_(n)NR⁶CO₂R⁷, O(CH₂)_(n)C(O)N(R⁷)₂, CF₃,CH₂CF₃, OCF₃, OCHCF₂, and OCH₂CF₃; wherein aryl, heteroaryl, cycloalkyl,and heterocyclyl are unsubstituted or substituted with one to threesubstituents independently selected from halogen, hydroxy, C₁₋₄ alkyl,trifluoromethyl, trifluoromethoxy, and C₁₋₄ alkoxy; and wherein anymethylene (CH₂) carbon atom in R⁵ and R⁸ is unsubstituted or substitutedwith one to two groups independently selected from halogen, hydroxy, andC₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) carbonatom are taken together with the carbon atom to which they are attachedto form a cyclopropyl group; each R⁶ is independently selected from thegroup consisting of C₁₋₈ alkyl, (CH₂)_(n)-aryl, (CH₂)_(n)-heteroaryl,and (CH₂)_(n)C₃₋₇ cycloalkyl; wherein alkyl and cycloalkyl areunsubstituted or substituted with one to five substituents independentlyselected from halogen, oxo, C₁₋₇ alkoxy, C₁₋₄ alkylthio, hydroxy, amino;and aryl and heteroaryl are unsubstituted or substituted with one tothree substituents independently selected from cyano, halogen, hydroxy,amino, carboxy, trifluoromethyl, trifluoromethoxy, C₁₋₄ alkyl, and C₁₋₄alkoxy; or two R⁶ groups together with the atom to which they areattached form a 5- to 8-membered mono- or bicyclic ring systemoptionally containing an additional heteroatom selected from O, S, andNC₁₋₄ alkyl; and each R⁷ is hydrogen or R⁶ and a compound selected fromthe group consisting of: (a) DP-IV inhibitors; (b) insulin sensitizersselected from the group consisting of (i) PPAR agonists and (ii)biguanides; (c) insulin and insulin mimetics; (d) sulfonylureas andother insulin secretagogues; (e) α-glucosidase inhibitors; (f) glucagonreceptor antagonists; (g) GLP-1, GLP-1 mimetics, and GLP-1 receptoragonists; (h) GIP, GIP mimetics, and GIP receptor agonists; (i) PACAP,PACAP mimetics, and PACAP receptor 3 agonists; (j) cholesterol loweringagents selected from the group consisting of (i) HMG-CoA reductaseinhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acidand salts thereof, (iv) PPARα agonists, (v) PPARα/γ dual agonists, (vi)inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterolacyltransferase inhibitors, and (viii) anti-oxidants; (k) PPARδagonists; (l) antiobesity compounds; (m) ileal bile acid transporterinhibitors; (n) anti-inflammatory agents excluding glucocorticoids; (o)protein tyrosine phosphatase-1B (PTP-1B) inhibitors; and (p)antihypertensives including those acting on the angiotensin or reninsystems, such as angiotensin converting enzyme inhibitors, angiotensinII receptor antagonists or renin inhibitors, such as captopril,cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril,zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan,tasosartan, telmisartan, and valsartan; said compounds beingadministered to the patient in an amount that is effective to treat saidcondition. 39-49. (canceled)